Pyrimidine derivatives

ABSTRACT

A compound of the following formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R4, R5, T, U, V, X, Y, Z, G, and Z are defined herein. It also discloses a method of treating an angiogenesis-related disorder, e.g., cancer or age-related macular degeneration, with such a compound.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 60/911,921, filed Apr. 16, 2007. The contents of the priorapplication are hereby incorporated by reference in their entireties.

BACKGROUND

Angiogenesis is a physiological process of growing new blood vesselsfrom pre-existing vessels. It takes place in a healthy subject to healwounds, i.e., restoring blood flow to tissues after injury or insult.

Excessive blood vessel growth may be triggered by certain pathologicalconditions such as cancer, age-related macular degeneration, rheumatoidarthritis, and psoriasis. As a result, new blood vessels feed diseasedtissues and destroy normal tissues. In cancer, new blood vessels alsoallow tumor cells to escape into the circulation and lodge in otherorgans.

Vascular endothelial growth factor (VEGF), a homodimeric glycoprotein,and its receptors, e.g., kinase insert domain receptor (KDR), constitutean important angiogenic pathway. Studies have shown that inhibition ofKDR resulted in endothelial cell apoptosis and, thus, suppression ofangiogenesis. See Rubin M. Tuder, Chest, 2000; 117: 281. KDR inhibitorsare therefore potential candidates for treating angiogenesis-relateddiseases.

SUMMARY

This invention is based on the discovery that a number of pyrimidinecompounds inhibit the activity of KDR.

One aspect of this invention features pyrimidine compounds of thefollowing formula (I):

in which each of X and Y, independently, is O, S, or NR, wherein R is H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, or aminosulfonyl; Z is CR′or N, wherein R′ is H, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heterocycloalkyl; V, U,and T together represent each

each of R₁, R₂, R₃, R₄, and R₆, independently, is H, halo, nitro, amino,cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy,alkoxycarbonyl, carbonylamino, sulfonylamino, aminocarbonyl, oraminosulfonyl; R₅ is alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl; and R₇ is alkyl.

Referring to formula (I), one subset of the compounds features that R₁,R₂, R₃, and R₄ is H and R₅ is aryl or heteroaryl, optionally substitutedwith halo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio,alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino,sulfonylamino, aminocarbonyl, or aminosulfonyl. Another subset featuresthat X is O or NH; Y is NH; V, U, and T together represent

in which R₆ can be H and R₇ can be methyl; or Z is CR′, in which R′ isH, halo, or alkyl.

The term “alkyl” herein refers to a straight or branched hydrocarbon,containing 1-10 carbon atoms. Examples of alkyl groups include, but arenot limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, andt-butyl. The term “alkoxy” refers to an —O-alkyl.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic,14-carbon tricyclic aromatic ring system wherein each ring may have 1 to4 substituents. Examples of aryl groups include, but are not limited to,phenyl, naphthyl, and anthracenyl.

The term “cycloalkyl” refers to a saturated and partially unsaturatedcyclic hydrocarbon group having 3 to 12 carbons. Examples of cycloalkylgroups include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system havingone or more heteroatoms (such as O, N, or S). Examples of heteroarylgroups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl,thienyl, quinolinyl, indolyl, and thiazolyl. The term “heteroaralkyl”refers to an alkyl group substituted with a heteroaryl group.

The term “heterocycloalkyl” refers to a nonaromatic 5-8 memberedmonocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ringsystem having one or more heteroatoms (such as O, N, or S). Examples ofheterocycloalkyl groups include, but are not limited to, piperazinyl,pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.Heterocycloalkyl can be a saccharide ring, e.g., glucosyl.

Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkoxymentioned herein include both substituted and unsubstituted moieties.Examples of substituents include, but are not limited to, halo,hydroxyl, amino, cyano, nitro, mercapto, alkoxycarbonyl, amido, carboxy,alkanesulfonyl, alkylcarbonyl, carbamido, carbamyl, carboxyl,thioureido, thiocyanato, sulfonamido, alkyl, alkenyl, alkynyl, alkyloxy,aryl, heteroaryl, cycloalkyl, heterocycloalkyl, in which alkyl, alkenyl,alkynyl, alkyloxy, aryl, heteroaryl cycloalkyl, and heterocycloalkyl mayfurther substituted.

The pyrimidine compounds described above include their pharmaceuticallyacceptable salts, hydrate and prodrug, if applicable.

Another aspect of this invention features a method of treating anangiogenesis-related disorder (e.g., cancer or age-related maculardegeneration). The method includes administering to a subject havingsuch an disorder an effective amount of one or more of theabove-described pyrimidine compounds.

Still another aspect of this invention features a method of inhibitingthe activity of kinase insert domain receptor by contacting the receptorwith an effective amount of a pyrimidine compound of formula (II):

in which R₁ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl; each of R₂ and R₃, independently, is H,halogen, nitro, amino, CN, hydroxy, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylcarbonyl,carboxy, or alkoxycarbonyl; each of X and Y, independently, is O, S, orNR₄, wherein R₄ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, or aminosulfonyl; and Ar is aryl or heteroaryl.

Referring to formula (II), one subset of the compounds features that Aris indolyl, indazolyl, benzoimidazolyl, or benzoxazolyl; X is O or NHand Y is NH; or R₁ is aryl or heteroaryl, optionally substituted withhalo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio,alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino,sulfonylamino, aminocarbonyl, or aminosulfonyl.

Exemplary compounds 1-317 are shown in the Detailed Description sectionbelow.

Yet another aspect of this invention features a method of inhibitingangiogenesis, or treating age-related macular degeneration, byadministrating to a subject in need thereof an effective amount of apyrimidine compound of formula (II) as described above.

Also within the scope of this invention are (1) a composition containingone or more of the pyrimidine compounds described above and apharmaceutically acceptable carrier for use in treating anangiogenesis-related disorder (e.g., such cancer or age-related maculardegeneration) and (2) use of one or more of the pyrimidine compounds forthe manufacture of a medicament for treating the disorder.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects and advantages of theinvention will be apparent from the description and from the claims.

DETAILED DESCRIPTION

The compounds described above can be synthesized from commerciallyavailable starting materials by methods well known in the art. As anexample, one can replace leaving groups (e.g., chloride, p-TsO, MeS, orMeSO₂) at the active N2, N4-positions of a suitable pyrimidine compoundwith nucleophilic groups such as amino or hydroxyl via, e.g.,Buchwald-Hartwig coupling reaction. The replacement can be firsteffected either at the N2 position or the N4 position.

The compounds thus obtained can be further modified at their peripheralpositions to provide the desired compounds.

Synthetic chemistry transformations useful in synthesizing desirablepyrimidine compounds are described, for example, in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995) and subsequent editions thereof.

Before use, the compounds can be purified by column chromatography, highperformance liquid chromatography, crystallization, or other suitablemethods.

The pyrimidine compounds described above, when contacting with KDR,inhibit this receptor's activity. An effective amount of one or more ofthese compounds can be therefore used to inhibit angiogenesis and treata subject having an angiogenesis-related disorder.

The term “an effective amount” refers to the amount of a pyrimidinecompound that is required to confer the intended effect in the subject.Effective amounts may vary, as recognized by those skilled in the art,depending on route of administration, excipient usage, and thepossibility of co-usage with other agents. The term “treating” refers toadministering one or more of the above-described pyrimidine compounds toa subject that has an angiogenesis-related disorder, or has a symptom ofthe disorder, or has a predisposition toward the disorder, with thepurpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate,improve, or affect the disorder, the symptoms of the disorder, or thepredisposition toward the disorder.

To practice this method, a composition having one or more of thepyrimidine compounds of this invention can be administered orally,parenterally, by inhalation spray, or via an implanted reservoir. Theterm “parenteral” as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraarticular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques.

An oral composition can be any orally acceptable dosage form including,but not limited to, tablets, capsules, emulsions and aqueoussuspensions, dispersions and solutions. Commonly used carriers fortablets include lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added to tablets. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions or emulsions areadministered orally, the active ingredient can be suspended or dissolvedin an oily phase combined with emulsifying or suspending agents. Ifdesired, certain sweetening, flavoring, or coloring agents can be added.

A sterile injectable composition (e.g., aqueous or oleaginoussuspension) can be formulated according to techniques known in the artusing suitable dispersing or wetting agents (such as, for example, Tween80) and suspending agents. The sterile injectable preparation can alsobe a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that canbe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium (e.g., synthetic mono- ordi-glycerides). Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions can also contain a long-chain alcohol diluent or dispersant,or carboxymethyl cellulose or similar dispersing agents.

An inhalation composition can be prepared according to techniques wellknown in the art of pharmaceutical formulation and can be prepared assolutions in saline, employing benzyl alcohol or other suitablepreservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

A topical composition can be formulated in form of oil, cream, lotion,ointment and the like. Suitable carriers for the composition includevegetable or mineral oils, white petrolatum (white soft paraffin),branched chain fats or oils, animal fats and high molecular weightalcohols (greater than C12). The preferred carriers are those in whichthe active ingredient is soluble. Emulsifiers, stabilizers, humectantsand antioxidants may also be included as well as agents imparting coloror fragrance, if desired. Additionally, transdermal penetrationenhancers may be employed in these topical formulations. Examples ofsuch enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762.Creams are preferably formulated from a mixture of mineral oil,self-emulsifying beeswax and water in which mixture the activeingredient, dissolved in a small amount of an oil, such as almond oil,is admixed. An example of such a cream is one which includes about 40parts water, about 20 parts beeswax, about 40 parts mineral oil andabout 1 part almond oil. Ointments may be formulated by mixing asolution of the active ingredient in a vegetable oil, such as almondoil, with warm soft paraffin and allowing the mixture to cool. Anexample of such an ointment is one which includes about 30% by weightalmond and about 70% by weight white soft paraffin.

A carrier in a pharmaceutical composition must be “acceptable” in thesense that it is compatible with active ingredients of the formulation(and preferably, capable of stabilizing it) and not deleterious to thesubject to be treated. For example, solubilizing agents, such ascyclodextrins (which form specific, more soluble complexes with one ormore of active pyrimidine compounds of the extract), can be utilized aspharmaceutical excipients for delivery of the active ingredients.Examples of other carriers include colloidal silicon dioxide, magnesiumstearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

Suitable in vitro assays can be used to preliminarily evaluate theefficacy of the above-described pyrimidine compounds in inhibiting theactivity of KDR or inhibiting the activity of VEGF. The compounds canfurther be examined for its efficacy in treating an angiogenesis-relateddisorder by in vivo assays. For example, the compounds can beadministered to an animal (e.g., a mouse model) having cancer and itstherapeutic effects are then accessed. Based on the results, anappropriate dosage range and administration route can also bedetermined.

Without further elaboration, it is believed that the above descriptionhas adequately enabled the present invention. The following specificexamples are, therefore, to be construed as merely illustrative, and notlimitative of the remainder of the disclosure in any way whatsoever.

EXAMPLE 1 Synthesis ofN4-(2-methyl-1H-indol-5-yl)-N2-phenylpyrimidine-2,4-diamine (Compound 1)

Et₃N (1 mmol) was added to a solution of 2,4-dichloropyrimidine (1 mmol)and 5-amino-2-methylindole (1 mmol) in 5 ml EtOH. The reaction mixturewas refluxed for 5 hours. After removal of the solvent in vacuo andaddition of H₂O, the mixture was extracted with EtOAc. The organiclayers were combined, washed with saturated NaCl solution, dried overanhydrous Na₂SO₄, and concentrated in vacuo. The resulting residue waspurified by column chromatography to giveN-(2-chloropyrimidin-4-yl)-2-methyl-1H-indol-5-amine in a yield of 80%.

N-(2-chloropyrimidin-4-yl)-2-methyl-1H-indol-5-amine (0.1 mmol) andaniline (0.1 mmol) were dissolved in 0.5 ml DMF. To this was addedp-TsOH monohydrate (0.2 mmol). The reaction mixture was stirred at 60°C. for 5 hours, diluted with water, and extracted with ethyl acetate.The organic layer was washed with water and brine sequentially, driedover anhydrous Na₂SO₄, and concentrated. The resulting residue waspurified by column chromatography to provide the title product in ayield of 85%.

¹H NMR (CD₃OD, 400 MHz): δ 7.831 (d, J=6.0 Hz, 1H), 7.633 (t, J=8.0-7.6Hz, 3H), 7.262 (t, J=8.4-7.6 Hz, 3H), 7.064 (d, J=6.8 Hz, 1H), 6.995((t, J=7.6-7.2 Hz,1H), 6.133 (t, J=6.4-2.0 Hz, 2H), 2.439 (s,3H); MS(m/e): 384.2 (M+1).

EXAMPLE 2-283 Synthesis of Compounds 2-283

Compounds 2-283 were each synthesized in a manner similar to thatdescribed in Example 1.

Com- ¹H NMR pound Name/Structure (400 MHz, δ ppm)/MS 2N2-(3-ethynylphenyl)-N4-(2-methyl-1H- indol-5-yl)pyrimidine-2,4-diamine 

(CD₃OD): 7.848 (d, J = 6.8 Hz, 1H), 7.730 (s,1H), 7.704 (d, J = 8.0 Hz,1H), 7.507 (s, 1H), 7.275 (d, J = 8.0 Hz, 1H), 7.200 (t, J = 8.0 Hz,1H), 7.093-7.036 (m, 2H), 6.639 (m, 2H), 2.425 (s, 3H); MS (m/e): 340.4(M + 1) 3 N2-(3-bromophenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 7.879 (s, 1H), 7.784 (d, J = 6.0 Hz, 1H), 7.437 (br, 1H), 7.373(s, 1H), 7.255 (d, J = 8.8 Hz, 1H), 7.079 (br, 2H), 6.968 (d, J = 8.4Hz, 1H), 6.133 (s, 1H), 6.041 (d, J = 6.4 Hz, 1H), 2.400 (s, 3H);MS(m/e): 394.3 (M) 4 N2-(3-fluorophenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 7.923 ( s, 1H), 7.759 (d, J = 6.0 Hz, 1H), 7.641 (d, J = 8.0Hz, 1H), 7.397 ( s, 1H), 7.247 (d, J = 8.4 Hz, 1H), 7.179-7.053 (m, 1H),6.963 (d, J = 8.4 Hz, 1H), 6.575 (t, J = 8.0 Hz, 1H), 6.125 (s, 1H),6.044 (d, J = 6.0 Hz, 1H), 2.395 (s, 3H); MS (m/e): 334.2 (M + 1) 5N2-(3-chlorophenyl)-N4-(2-methyl-1H- indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 7.838 (d, 7 = 6.8 Hz, 1H), 7.746 (s, 1H), 7.526 (br, 2H), 7.298(d, 7 = 8.4 Hz, 1H), 7.212 (t, J = 8.0 Hz, 1H), 7.102 (d, J = 8.4 Hz,1H), 7.001 (d, J = 8.0 Hz, 1H), 6.217 (d, J = 6.0 Hz, 1H), 6.133 (s,1H), 2.436 (s, 3H); MS (m/e): 350.2 (M + 1) 6N4-(2-methyl-1H-indol-5-yl)-N2-(3-(trifluoromethyl)phenyl)pyrimidine-2,4- diamine  

(CD₃OD): 8.045 (d, J = 7.2 Hz, 1H), 7.788 (d, J = 6.0 Hz, 2H), 7.529 (s,1H), 7.366 (d, J = 6.8 Hz, 1H), 7.276 (d, J = 8.4 Hz, 1H), 7.228 (d, J =7.2 Hz, 1H), 7.083 (d, J = 1.2 Hz, 1H), 6.190 ((d, J = 6.4 Hz, 1H),6.115 (s, 1H), 2.440 (s, 3H). MS(m/e): 384.2 (M + 1) 7N4-(2-methyl-1H-indol-5-yl)-N2-(3-(methylsulfonyl)phenyl)pyrimidine-2,4- diamine  

(CD₃OD): 11.471 (s, 1H), 9.461 (s, 1H), 9.364 (s, 1H), 8.441 (s, 1H),8.236 (s, 1H), 7.988 (d, J = 5.6 Hz, 1H), 7.396 (M, , 5H), 7.303 (d, J =8.4 Hz, 1H), 6.255(d, J = 5.6 Hz, 1H), 3.111 (s, 3H), 2.456 (s, 3H).MS(m/e): 393.2 (M + 1) 8 N2-(3-methoxylphenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 8.050 (s, 1H), 7.943 (d, J = 6.0 Hz, 1H), 7.440-7.362 (m, 3H),7.293 (s, 1H), 7.223(t, J = 8.0 Hz, 2H), 7.122 (d, J = 7.6 Hz, 1H),7.0211 (d, J = 6.8 Hz, 1H), 6.808 (s, 1H), 6.680 (d, J = 6.4 Hz, 1H),6.222 (s, 1H), 6.068(d, J = 5.6 Hz, 1H), 3.790 (s, 3H), 2.472 (s, 3H);MS (m/e): 345.9 (M + 1) 9 ethyl 1-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzyl)piperidine-4-carboxylate  

(CD₃OD): 8.019 (s, 1H), 7.889 ( d, J = 5.6 Hz, 1H), 7.554 (s, 1H), 7.399( d, J = 8.0 Hz, 1H), 7.328 ( d, J = 8.4 Hz, 1H), 7.278 ( t, J = 8.0 Hz,1H), 7.101 ( d, J = 8.0 Hz, H), 7.002 (d, J = 7.2 Hz, 1H), 6.180 (d, J =6.0 Hz, 1H), 6.141 (s, 1H), 4.166 ( q, J = 7.2 Hz, 1H), 3.586 (s, 2H),2.973-2.943 (m, 2H), 2.462 (s, 3H), 2.316 (br, 1H), 2.089 (m, 2H),1.939-1.885 (m, 2H), 1.741- 1.653 (m, 2H), 1.272 (t, J = 7.2 Hz, 2H); MS(m/e): 485.4 (M + 1) 10 N2,N4-bis(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 7.675 ( d, J = 6.4 Hz, 1H), 7.625 (s,1H), 7.577 (br, 1H),7.266-7.219 (m, 2H), 7.068-7.051 (m, 1H), 6.116 (d, J = 6.0 Hz, 1H),6.072 (s, 1H), 6.014 (s, 1H) 2.435 (s, 3H), 2.425 (s, 3H); MS (m/e):369.3 (M + 1) 11 N2-(1H-indazol-5-yl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 12.385 (s, 1H), 10.928 (s, 1H), 9.120 (s, 1H), 9.003 (s, 1H),8.259 (s, 1H), 7.920( d, J = 6.0 Hz, 1H), 7.758 (s, 1H), 7.667 (s, 1H),7.541 (d, J = 8.8 Hz, 2H), 7.399 (d, J = 8.8 Hz, 1H), 7.242 (d, J = 8.8Hz, 1H), 7.151 (d, J = 8.8 Hz, 1H), 6.142 (d, J = 6.0 Hz, 1H), 6.017 (s,1H), 2.389 (s, 3H). MS (m/e): 356.3 (M + 1) 12N2-(1H-benzo[d]imidazol-5-yl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

(CD₃OD): 10.853 (s, 1H), 9.033(s, 1H), 8.956 (s,1 H), 8.077 (br, 2H),7.925( d, J = 6.0 Hz, 1H), 7.736 (s, 1H), 7.533 ( d, J = 8.0 Hz, 1H),7.444 ( d, J = 8.8 Hz, 1H), 7.214- 7.144 (m, 2H), 6.131 (d, J = 6.0 Hz,1H), 6.020 (s, 1H), 2.372 (s, 3H); MS (m/e): 356.3 (M + 1) 13N2-(2-methoxyphenyl)-N4-(2-methyl- 1H-indol-5-yl)pyrimidine-2,4-diamine 

(CD₃OD): 8.496 (s, 1H), 8.002( d, J = 6.0 Hz, 2H), 7.446 ( s, 1H), 7.047(dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.981-6.957 (m, 2H), 6.913-6.771 (m,1H), 6.889 (s, 1H) 7 6.243 (s, 1H), 6.083 (d, J = 6.0 Hz, 1H), 3.910 (s,3H), 2.490 (s, 3H). MS (m/e): 346.2 (M + 1) 14N2-(2-chlorophenyl)-N4-(2-methyl-1H- indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 8.385 ( d, J = 6.0 Hz, 1H), 7.914 ( s, 1H), 7.849 (s, 1H),7.325 (d, J = 7.6 Hz, 1H), 7.237 (d, J = 8.4 Hz, 1H), 7.182 (t, J = 7.6Hz, 1H), 6.945-6.870 (m, 2H), 6.119 (s, 1H), 6.070 (d, J = 6.0 Hz, 1H),2.397 (s, 3H); MS (m/e): 350.1 (M + 1) 15N2-(2-bromophenyl)-N4-(2-methyl-1H- indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 10.860 (s, 1H), 9.204 (s, 1H), 8.140 (d, J = 8.4 Hz, 1H), 7.916(d, J = 5.6 Hz, 2H), 7.651 (d, J = 7.6 Hz, 2H), 7.334 (t, J = 7.6 Hz,1H), 7.184 (d, J = 8.8 Hz, 1H), 7.038 (br, 2H), 6.192 (d, J = 6.0 Hz,1H), 6.012 (s, 1H), 2.369 (s, 3H); MS (m/e): 394.3 (M) 16N2-(4-fluorophenyl)-N4-(2-methyl-1H- indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 10.889 (s, 1H), 9.256 (s, 1H), 9.245 (s, 1H), 7.966 (d, J = 5.6Hz, 1H), 7.752 (m, J = 8.4-3.6 Hz, 2H), 7.236 (d, J = 5.4 Hz 1H),7.133(m, J = 8.4-3.6 Hz, 3H), 6.086 (d, J = 5.6 Hz, 1H), 6.050 (s, 1H), 2.402(s, 3H); MS (m/e): 334.2 (M + 1) 17 methyl 2-(4-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)acetate  

(CD₃OD): 10.907 (s, 1H), 9.132(s, 1H), 9.015 (s, 1H), 7.914 (s, 1H),7.713 (d, J = 6 Hz, 1H), 7.498 (d, J = 6.8 Hz, 1H), 7.217 (d, J = 7.2Hz, 1H), 7.127 (m, 4H), 6.149 (d, J = 6 Hz, 1H), 6.067 (s, 1H), 2.384(s, 3H), 2.272 (s, 3H), 1.288 (s, 2H). MS (m/e): 387.2 (M + 1) 18N4-(2-methyl-1H-indol-5-yl)-N2-(4- phenoxyphenyl)pyrimidine-2,4-diamine 

(CD₃OD): 10.855 (s, 1H), 9.098 (s, 1H), 9.065 (s, 1H), 7.909 (d, J = 5.6Hz, 1H), 7.786 (d, J = 8 Hz, 2H), 7.365 (t, J = 7.6 Hz, 2H), 7.346 (s,1H), 7.201 (d, J = 8.8 Hz, 1H), 7.086 (m, 2H), 6.962 (d, 8 Hz, 2H),6.895 (d, J = 8 Hz, 2H), 6.137 (d, J = 5.6 Hz, 1H), 6.021(s, 1H), 2.331(s, 3H). MS (m/e): 407.5 (M + 1) 19 N2-(4-methoxyphenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 11.097 (s, 1H), 9.479 (s, 1H), 9.243 (s, 1H), 8.090 (d, J =6Hz, 1H), 7.923 (s, 1H), 7.822 (m, 2H), 7.420 (d, 8.8 Hz, 1H), 7.307 (s,1H), 7.025 (d, J = 8.8 Hz, 2H), 6.340 (m, 1H), 6.265 (s, 1H), 3.941 (s,3H), 2.591 (s, 3H); MS (m/e): 345.4 (M + 1) 20N4-(2-methyl-1H-indol-5-yl)-N2-(4-(2- morpholinoethoxy)phenyl)pyrimidine- 2,4-diamine  

(CD₃OD): 10.899 (s, 1H), 9.074 (s, 1H), 8.823 (s, 1H), 7.869 (d, J = 6Hz, 1H), 7.713(s, 1H), 7.621 (d, J = 8.8 Hz, 2H), 7.200(d, J = 8.4 Hz,1H), 7.080 (s, 1H), 6.784 (m, 2H), 6.101 (d, J = 5.6 Hz, 1H), 6.025 (s,1H), 4.034 (t, J = 5.6 Hz, 2H), 3.585 (t, J = 4.8 Hz, 4H), 2.679 (t, J =5.6 Hz, 2H), 2.475 (t, J = 6.4 Hz, 4H), 2.375 (s, 3H); MS: 444.5 (M + 1)21 N2-(3,4-difluorophenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 11.234 (s, 1H), 9.886 (s, 1H), 9.754 (s, 1H), 7.966 (d, J = 5.6Hz, 2H), 7.752 (s, 1H), 7.393 (m, J = 8.4-3.6 Hz, 3H), 7.133 (d, J = 5.6Hz, 1H), 6.251 (d, J = 4.5 Hz, 1H), 6.1.9 (s, 1H), 2.402 (s, 3H); MS(m/e): 352.2 (M + 1) 22 N2-(3,5-dimethylphenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 10.863 (s, 1H), 9.05l (s, 1H), 8.841 (s, 1H), 7.905 (d, J = 6Hz, 1H), 7.633 (s, 1H), 7.361 (s, 1H), 7.207 (m 2H), 6.507 (s, 1H),6.118 (d, J = 5.6 Hz, 1H), 6.032 (s, 2H), 2.370 (s, 3H), 2.171 (s, 6H);MS (m/e): 343.4 (M + 1). 23 2-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)ethanol  

(CD₃OD): 7.939(d, J = 8.0 Hz, 1H), 6.923 (d, J = 6.8 Hz, 2H), 6.437 (s,1H), 6.328 (d, J = 7.6 Hz, 2H), 6.218 (s, 1H), 6.231 (d, J = 5.6 Hz,1H), 5.726 (d, J = 7.2 Hz, 1H), 3.735 (t, J = 7.2-6.4 Hz, 3H), 3.225 (t,J = 6.8-5.6 Hz, 3H), 2.247 (s, 3H); MS (m/e): 384.1 (M + 1) 24N4-(2-methyl-1H-indol-5-yl)-N2-(2-morpholinoethyl)pyrimidine-2,4-diamine  

(CD₃OD): 7.796 (d, J = 6.0 1 Hz, H), 7.497 (s, 1H), 7.246 (d, J = 8.8Hz, 1H), 7.076 (d, J = 2.8 Hz, 1H), 6.148 (s, 1H), 5.625 (d, 7 = 4.8 Hz,1H), 3.760 (m, J = 3.2-2.8 Hz, 4H), 3.165 (t, J = 3.2- 2.4,2H), 2.619(t, J = 2.0- 0.8 Hz, 2H), 2.447 (m, J = 2.0-1.2 Hz, 4H), 2.317 (s, 3H).MS (m/e): 353.2 (M + 1) 25 N-cyclopropyl-2-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)acetamide  

(DMSO-d₆,): 7.920 (d, J = 5.6 Hz, 1H), 7.700 (m, 2H), 7.546 (s, 1H),7.220 (d, J = 8.0 Hz, 1H), 7.120 (m, 2H), 6.778 (d, J = 8.0 Hz, 1H),6.200 (d, J = 6.0 Hz, 1H), 6.066 (s, 1H), 3.027 ( s, 2H), 2.593 (m, 1H),2.380 ( s, 3H), 0.608 (m, 2H), 0.404 (m, 2H ). MS (m/e): 413.5 (M + 1).26 N2-(3-(2- (dimethylamino)ethylsulfonyl)phenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine- 2,4-diamine  

(CD₃OD): 8.237 (s, 1H), 8.042 (d, J = 6.8 Hz 1H), 7.867 (d, J = 6.0 Hz,1H), 7.477 (s, 1H), 7.465 (br, 2H), 7.253 (d, J = 8.8 Hz, 1H), 7.028 (d,J = 8.0 Hz 1H), 6.141 (d, J = 5.6 Hz 1H), 6.088 (s, 1H), 3.230 (t, J =7.6 Hz, 2H), 2.666 (t, J = 7.2 Hz , 2H), 2.409 (s, 3H) , 2.165 (s, 6H);MS: 451.4 (M + 1). 27 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(1-(methylsulfonyl)piperidin-4- yloxy)phenyl)pyrimidine-2,4-diamine  

(DMSO-d6): 10.976 (s, 1 H), 9.240 (s, 1 H), 9.036 (s, 1 H), 7.054-8.014(m, 7H), 6.401- 6.564 (m, 1H), 6.114- 6.278 (m, 1H), 6.012- 6.073 (m,1H), 4.224- 4.383 (m, 1H), 3.110- 3.209 (m, 2H), 2.770- 2.886 (m, 2H),2.370 (s, 3H), 1.806-1.970 (m, 2H), 1.578-1.712 (m, 1H); MS (m/e): 493.5(M + 1) 28 N-(3-(4-(2-methyl-1H-indol-5- ylamino)pyrimidin-2-ylamino)phenyl)methanesulfonamide  

(CD₃OD): 7.856 (d, J = 6.0 Hz, 1H), 7.652 (s, 1H), 7.543 (s, 1H), 7.432(dd, J = 8.4 Hz, 1H), 7.271 (d, J = 8.4 Hz, 1H), 7.196 (t, J = 8.0 Hz,1H), 6.882 (dd, J = 8.0 Hz, 2H), 6.130 (d, J = 6.0 Hz, 2H), 2.440 (s,3H), 2.172 (s, 3H); MS (m/e): 409.3 (M + 1) 29N4-(2-methyl-1H-indol-5-yl)-N2-(3-(2-morpholinoethoxy)phenyl)pyrimidine- 2,4-diamine  

(DMSO-d₆,): δ 10.825 (s, 1H), 9.023 (s, 1H), 8.986 (s, 1H), 7.927 (d, J= 5.6 Hz, 1H), 7.703 (s, 1H), 7.429 (s, 1H), .351 (d, J = 2.4 Hz, 1H),7.208 (d, J = 8.8 Hz, 1H), 7.076 (m, J = 8 Hz, 2H), 6.469 (dd, J = 8,2.4 Hz, 1H), 6.118 (d, J = 2 Hz, 1H), 6.057 (s, 1H), 3.933 (t, J = 5.6Hz, 2H), 3.551 (t, J = 4.8 Hz, 4H), 2.591 (t, J = 5.6 Hz, 2H), 2.401 (t,J = 4.8 Hz, 4H), 2.379 (s, 3H); MS (m/e): 444.5 (M + 1). 30N2-(3-(3-(dimethylamino) propoxy)phenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 10.836 (s, 1H), 9.021 (s, 1H), 8.983 (s, 1H), 7.926 (d, J = 6Hz, 1H), 7.691 (s, 1H), 7.419 (s, 1H), 7.345 (d, J = 8.4 Hz, 1H), 7.212(d, J = 8.4 Hz, 1H), 7.079 (m, 2H), 6.444 (dd, J = 8, 2.4 Hz, 1H), 6.118(d, J = 6 Hz, 1H), 6.062 (s, 1H), 3.835 (t, J = 6 Hz, 2H), 2.317 (s,3H), 2.318 (t, J = 7.2 Hz, 2H), 2.154 (s, 6H), 1.767 (t, J = 7.2 Hz,2H); MS (m/e): 416.5 (M + 1). 31

  2-(3-(4- (2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)phenoxy)ethanol (CD₃OD): 10.902 (s, 1H), 9.087 (s, 1H), 8.986(s, 1H), 7.917 (d, J = 4 Hz, 1H), 7.683(s, 1H), 7.405 (m, 2H), 7.227 (m,1H), 7.104 (m, 1H), 6.458 (d, J = 8 Hz, 1H), 6.141 (s, 1H), 6.050 (m,2H), 5.594 (m, 1H), 3.873 (t, J = 5.6 Hz, 2H), 3.653 (t, J = 6 Hz, 2H),2.376 (s, 3H); MS (m/e): 375.4 (M + 1) 32 2-(2-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenoxy)ethanol  

(CD₃OD): 10.851 (s, 1H), 9.117 (s, 1H), 8.431 (d, J = 8.0 Hz 1H), 7.938(d, J = 6.0 Hz, 1H), 7.869 (s, 1H), 7.689 (br, 1H), 7.228 (d, J = 8.8Hz, 1H), 6.983- 7.053 (m, 2H), 6.836~6.923 (m, 2H), 6.147 (d, J = 6.0 Hz1H), 6.079 (s, 1H), 5.137 (t, J = 5.6 Hz 1H), 4.061 (q, J = 11.2 Hz, 1.2Hz 2H), 3.767 (q, J = 9.6 Hz , 5.6 Hz 2H), 2.389 (s, 3H); MS (m/e):376.3 (M + 1). 33 N4-(2-methyl-1H-indol-5-yl)-N2-(2-(2-morpholinoethoxy)phenyl)pyrimidine- 2,4-diamine  

(CD₃OD): 10.845 (s, 1H), 9.112 (s, 1H), 8.377 (d, J = 7.6 Hz 1H), 7.935(d, J = 6.0 Hz, 1H), 7.823 (s, 1H), 7.647 (br, 1H), 7.219 (d, J = 8.8Hz, 1H), 7.061 (d, J = 8 Hz, 2H), 6.889-6.950 (m, 2H), 6.147 (d, J = 6.0Hz 1H), 6.074 (s, 1H), 4.182 (t, J = 6.0 Hz 2H), 3.592 (t, J = 4.8 Hz,4H), 2.692 (t, J = 5.2 Hz, 2H), 2.471 (br, 4H), 2.388 (s, 3H); MS(m/e):445.3 (M + 1). 34 N-methyl-3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)benzamide  

(DMSO-d₆): δ 11.015 (s, 1H), 10.776 (s, 1H), 10.593 (s, 1H), 8.493 (d, J= 4 Hz, 1H), 7.938 (m, 2H), 7.803 (d, J = 2 Hz, 1H), 7.651 (m, 2H),7.374 (m, 1H), 7.210 (m, 2H), 6.467 (m 1H), 6.046 (s, 1H), 2.779 (d, 4.4Hz, 3H), 2.379 (s, 3H); MS (m/e): 373.4 (M + 1). 353-(4-(2-methyl-1H-indol-5- ylamino)pyrimidin-2-ylamino)-N-(2-(piperidin-1-yl)ethyl)benzamide  

(CD₃OD): 10.832 (s, 1H), 9.156 (s, 1H), 9.056 (s, 1H), 8.157 (s, 1H),8.054 (s, 1H), 7.946 (m, 2H), 7.700 (b, 1H), 7.319 (m, 2H), 7.199 (m,2H), 6.159 (s, 1H), 6.052 (s, 1H), 3.180 (t, J = 5.6 Hz, 2H), 2.378 (s,3H), 1.480(s, 6H), 1.372 (s, 4H), 1.229 (s, 2H). MS (m/e): 469.6 (M + 1)36 N-(2-(dimethylamino)ethyl)-3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzamide  

(CD₃OD): 10.846 (s, 1H), 9.149 (s, 1H), 9.077 (s, 1H), 8.181 (t, J = 5.6Hz, 1H), 8.036 (m, 2H), 7.934 (m, 1H), 7.706 (b, 1H), 7.340 (m, 1H),7.270 (m, 1H), 7.203 (m, 1H), 7.137 (m, 1H), 6.160 (d, J = 5.6 Hz, 1H),6.054 (s, 1H), 3.313 (t, J = 6.4 Hz, 2H), 3.175 (t, J = 5.6 Hz, 2H),2.376 (s, 3H), 2.175 (s, 6H). MS (m/e): 429.5 (M + 1) 37N2-(3-(4-methoxyphenyl)-1H-pyrazol-5- yl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

(DMSO-d6): δ 12.354 (s, 1H), 10.911 (s, 1H), 8.985 (br, 2H), 7.901 (s,1H), 7.599 (br, 2H), 7.259 (d, J = 8.4 Hz, 1H), 7.037 (s, 1H),6.941-6.913 (m, 2H), 6.099 (br, 2H), 3.787 (s, 3H), 2.493 (s, 3H); MS(m/e): 412.8 (M + 1). 38 N-(3-ethyny]phenyl)-4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2-amine  

(CD₃OD): 8.190 (d, J = 6.0 Hz, 1H), 8.098 (s, 1H), 7.612 (s, 1H), 7.489( d, J = 8.0 Hz, 1H), 7.339-7.284 (m, 2H), 7.053 (t, J = 8.4 Hz, 1H),6.937 (dd, J = 8.4 Hz, 2.0 Hz, 2H), 6.294 (d, J = 6.0 Hz, 2H), 6.262 (s,1H), 2.495 (s, 3H); MS (m/e): 341.1 (M + 1) 39N-(4-methoxyphenyl)-4-(2-methyl-1H- indol-5-yloxy)pyrimidin-2-amine  

(CD₃OD): 8.198 (d, J = 6.4 Hz, 1H), 7.974 (s, 1H), 7.363-7.283 (m, 2H),6.935 (m, 2H), 6.742 ( t, J = 8.4 Hz, 1H), 6.260 (s, 1H), 6.200 (d, J =5.6 Hz, 1H), 3.771 (s, 3H), 2.493 (s, 3H). MS (m/e): 347.2 (M + 1). 414-(2-methyl-1H-indol-5-yloxy)-N-(4- phenoxyphenyl)pyrimidin-2-amine  

(CD₃OD): 8.201 (d, J = 5.6 Hz, 1H), 7.373 (m, J = 8.8-5.2 Hz, 4H), 7.188(d, J = 2.0 Hz, 1H), 7.081 (t, J = 7.2-6.8 Hz, 1H), 6.989 (d, J = 3.2Hz, 2H), 6.890 (d, J = 8.4 Hz, J = 2.0 Hz, 1H), 6.644 (d, J = 9.2 Hz,2H), 6.323 (d, J = 6.4 Hz, 1H), 6.137 (s, 1H), 2.376 (s, 3H). MS (m/e):409.3 (M + 1). 42 N-(3-methoxyphenyl)-4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2-amine  

(CD₃OD): 8.236 (d, J = 5.2 Hz, 1H), 7.983 (s, 1H), 7.314-7.283 (m, 2H),7.239 (br, 1H), 7.063 ( t, J = 8.0 Hz, 1H), 6.981 (d, J = 8.0 Hz, 1H),6.981 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 6.528 (d, J = 8.0 Hz, 1H), 6.278-6.253 (m, 1H), 3.571 (s, 1H), 2.493 (s, 3H). MS (m/e): 347.2 (M + 1). 434-(2-methyl-1H-indol-5-yloxy)-N-(3-(3- (thiomorpholino-1′,1′-dioxide)propoxy)phenyl)pyrimidin-2- amine  

(CD₃OD): 8.298 (s, 1H), 7.996 (d, J = 5.6 Hz, 1H), 7.385 (d, J = 8.4 Hz,1H), 7.197 (t, J = 8.0 Hz, 1H), 7.094 (d, J = 8.4 Hz, 2H), 6.791 (s,1H), 6.543 (d, J = 8.0 Hz, 1H), 6.333 (s, 1H), 5.995 (d, J = 6.0 Hz,1H), 5.321 (s, 1H), 3.974 (t, J = 5.6 Hz, 1H), 3.077 (m, 8H), 2.699 (t,J = 6.8 Hz, 1H), 2.468 (s, 3H), 1.926 (t, J = 6.8 Hz, 2H); 44N-methyl-3-(4-(2-methyl-1H-indol-5- yloxy)pyrimidin-2-ylamino)benzamide 

(DMSO-d6): 11.130 (s, 1H), 9.631 (s, 1H), 8.324 (d, J = 4.2 Hz, 1H),8.309 (s, 1H), 7.994 (s, 1H), 7.741 (s, 1H), 7.308 (d, J = 9.2 Hz, 1H),7.219 (d, J = 1.6 Hz, 1H), 7.052 (t, J = 2.0-0.8 Hz, 2H), 6.932 (m, 1H),6.272 (d, J = 3.6 Hz, 1H), 6.140 (d, J = 4.2 Hz, 1H), 5.249 (s, 1H),2.801 (s, 3H), 2.437 (s, 3H), 2.401 (m, 2H); MS (m/e): 374.3 (M + 1) 45trifluoro-N-(4-(4-(2-methyl-1H-indol-5- yloxy)pyrimidin-2-ylamino)phenyl)methanesulfonamide  

(DMSO-d6): 11.248 (s, 1H), 9.304 (s, 1H), 9.153 (8, 1H), 7.960 (s, 1H),7.913 (d, J = 6.0 Hz, 1H), 7.543 (d, J = 4.4 Hz, 2H), 7.132 (d, J = 8.4Hz, 1H), 7.063 (m, 1H), 6.910 (t, J = 3.6 Hz, 2H), 6.217 (s, 1H), 6.106(t, J = 1.6-2.4 Hz, 1H), 2.411 (s, 3H) MS (m/e): 464.4 (M + 1) 46(S)-4-(2-methyl-1H-indol-5-yloxy)-N-(3-(pyrrolidin-3-yloxy)phenyl)pyrimidin-2- amine  

(DMSO-d6): 11.122 (s, 1 H), 9.515 (s, 1 H), 8.306 (d, J = 5.6 Hz, 1H),7.156-7.332 (m, 4H), 6.951 (t, J = 8.0 Hz, 1H), 6.827 (dd, J = 8.4 Hz,2.0 Hz, 1H ), 6.427 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.267 (d, J = 6.0 Hz,1H), 6.139 (s, 1H), 6.639 (m, 2H), 4.652-4.711 (m, 1H), 2.964-3.154 (m,4H), 2.401 (s,3H), 1.958- 1.993 (m, 1H), 1.825- 1.898 (m, 1H); MS (m/e):402.4 (M + 1) 47

  N- methyl-3-(4-(2-methyl-1H-indol-5- yloxy)pyrimidin-2-ylamino)benzenesulfonamide (CDCl₃): 8.290 (d, 1H), 8.115 (s, 1H), 7.994(s, 1H), 7.504 (d, J = 8, 1H), 7.409 (m, 2H), 7.247 (d, J = 8, 1H),6.958 (m, J = 10.8), 6.403 (d, J = 5.6, 1H), 6.254 (s, 1H). 2.505 (s,3H), 2.478 (d, J = 5.6, 3H). MS (m/e): 410.1 (M + 1) 48N-(4-(4-(2-methyl-1H-indol-5- yloxy)pyrimidin-2-ylamino)phenyl)methanesulfonamide  

(CD₃OD): 11.204 (s, 1H), 9.120 (s, 1H), 8.837 (s, 1H), 7.959 (d, J = 5.6Hz, 1H), 7.791 (d, J = 6.8 Hz, 2H), 7.144 (s, 1H), 7.026 (d, J = 7.6 Hz,2H), 6.922 (d, J = 7.2 Hz, 1H), 6.210 (s, 1H), 6.115 (s, 1H), 4.007 (s,3H), 2.405 (s, 3H); MS (m/e): 358.2 (M + 1). 492-(3-(4-(2-methyl-1H-indol-5- yloxy)pyrimidin-2-ylamino)phenyl)-N-(2-morpholinoethyl)acetamide  

(CD₃OD): 11.211 (s, 1H), 8.935 (s, 1H), 8.760 (s, 1H), 7.959 (t, J =8.8- 5.6 Hz, 2H), 7.376 (s; 1H), 7.276 (d, J = 7.6 Hz, 1H), 7.120 (t, J= 8.8- 4.4 Hz, 1 H), 6.896 (t, J = 8.0 Hz, 2H), 6.403 (t, J = 2.0-1.6Hz, 1H), 6.205 (s, 1H), 6.004 (s, 1H), 3.560 (s, 3H), 2.405 (s, 3H); MS(m/e); 364.2 (M + 1). 50 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(2-(methylsulfonyl)ethoxy)phenyl)pyrimidin- 2-amine  

(CD₃OD): 8.345 (s, 1H), 8.049 (s, 1H), 7.915 (d, J = 6.0 Hz, 1H), 7.826(s, 1H), 7.58 (d, J = 8.8 Hz, 1 H), 7.535 (m, J = 7.2-6.8 Hz, 1H), 7.433(d, J = 7.6 Hz, 2H), 7.103 (d, J = 7.6 Hz, 1H), 6.241 (s, 1H), 2.460 (s,3H); MS (m/e): 402.2 (M + 1). 51 N-methyl(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)phenyl) methanesulfonamide  

11.217 (s, 1H), 8.998 (s, 1H), 8.789 (s, 1H), 7.947 (d, J = 5.6 Hz, 1H),7.595 (m, J = 7.8- 1.6 Hz, 2H), 7.133 (d, J = 8.0 Hz, 2H), 7.000, (s,1H), 6.721 (d, J = 2.8 Hz, 1H), 6.211 (s, 1H), 6.021 (s, 1H), 2.403 (s,3H), 2.346 (s, 3H); MS (m/e): 380.2 (M + 1). 52N4-(4-fluoro-2-methyl-1H-indol-5-yl)- N2-(3-fluorophenyl)pyrimidine-2,4-diamine  

(CD₃OD): 11.234 (s, 1H), 9.256 (s, 1H), 8.898 (s, 1H), 7.966 (d, J = 5.6Hz, 1H), 7.752 (d, J = 8.4 Hz, 1H), 7.393 (t, J = 8.4 Hz, 1H), 7.133 (m,J = 8.4- 3.6 Hz, 3H), 6.612 (t, J = 7.6-1.2 Hz, 1H), 6.239 (s, 1H),6.050 (s, 1H), 2.402 (s, 3H); MS (m/e): 352.2 (M + 1). 53N2-(3-chloropheny)-N4-(4-fluoro-2- methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

(CD₃OD): 11.221 (s, 1H), 8.965 (s, 1H), 8.775 (s, 1H), 7.927 (d, J = 6.0Hz, 1H), 7.619 (d, J = 8.0 Hz, 2H), 7.128 (m, J = 8.0-7.6 Hz, 2H), 6.958(d, J = 7.8 Hz, 2H), 6.210 (s, 1H), 2.411 (s, 3H); MS (m/e): 368.2 (m/e)(M + 1). 54 2-(4-(4-fluoro-2-methyl-1H-indol-5- ylamino)pyrimidin-2-ylamino)benzonitrile  

(CD₃OD): 11.248 (s, 1H), 9.412 (s, 1H), 8.959 (s, 1H), 8.208 (s, 1H),7.936 (d, J = 7.2 Hz, 1H), 7.562 (d, J = 5.6 Hz, 1H), 7.287 (s, 2H),7.164 (d, J = 8.4 Hz, 2H), 6.233 (s, 1H), 6.075 (s, 1H), 2.399 (s, 3H);MS (m/e): 359.2 (M + 1). 55 N2-(3,5-dimethylphenyl)-N4-(4-fluoro-2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

(CD₃OD): 11.200 (s, 1H), 8.806 (s, 1H), 8.745 (s, 1H), 7.911 (d, J = 6.0Hz, 1H), 7.216 (s, 2 H) 7.117 (t, J = 8.8-7.8 Hz, 2H), 6.396 (s, 1H),6.181 (s, 1H), 6.010 (s, 1H), 2.381 (s, 3H); 1.985 (s, 6H); MS (m/e):362.3 (M + 1). 56 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(2-(trifluoromethyl) phenyl)pyrimidine-2,4-diamine  

(CD₃OD): 11.211 (s, 1H), 8.898 (s, 1H), 8.209 (s, 1H), 7.939 (t, J =9.6- 6.0 Hz, 2H), 7.270 (1, J = 8.4-1.6 Hz, 1 H) 7.126 (s, 2H), 6.998(m, J = 2.0-1.2 Hz, 2H), 6.225 (s, 1H), 6.035 (s, 1H), 2.402 (s, 3H); MS(m/e): 402.2 (M + 1). 57 N2-(2-chlorophenyl)-N4-(4-fluoro-2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

(CD₃OD): 11.231 (s, 1H), 8.922 (s, 1H), 8.143 (d, J = 8.0 Hz, 1H), 7.936(s, J = 5.6 Hz, 1H), 7.790 (s, 1H), 7.424 (d, J = 8.4 Hz, 1H), 7.101 (m,J = 8.4-7.2 Hz, 2H), 6.993 (t, J = 8.8- 7.2 Hz, 1H), 6.216 (s, 1H),6.093 (m, J = 7.2- 10.0 Hz, 1H), 4.043 (s, J = 7.8 Hz, 1H), 2.402 (s,3H); MS (m/e): 368.2 (M + 1). 59 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(4-methoxyphenyl)pyrimidine-2,4- diamine  

11.222 (s, 1H), 8.796 (s, 1H), 8.729 (s, 1H), (CD₃OD): 7.959 (s, 1H),7.892 (d, J = 5.6 Hz, 1H), 7.547 (d, J = 8.8 Hz, 2 H) 7.075 (s, 1H),6.646 (d, J = 7.6 Hz, 2H), 6.222 (s, 1H), 5.567 (s, 1H), 3.658 (s, 3H),2.406 (s, 3H); MS (m/e): 402.2 (M + 1). 60N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(4-phenoxyphenyl)pyrimidine-2,4- diamine  

(CD₃OD): 11.190 (s, 1H), 9.046 (s, 1H), 8.801 (s, 1H), 7.959 (s, 1H),7.931 (d, J = 6.0 Hz, 1H), 7.681 (d, J = 7.2 Hz, 2H), 7.361 (t, J =8.0-7.6 Hz, 2H), 7.114 (m, J = 8.4- 7.2 Hz, 3H), 6.903 (d, J = 8.0 Hz,2H), 6.755 (d, J = 7.2 Hz, 2H), 6.179 (s, 1H) , 6.024 (s, 1H), 2.338 (s,3H). MS (m/e): 426.2 (M + 1). 612-(1-(3-(4-(4-fluoro-2-methyl-1H-indol-5- ylamino)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)ethanol  

(CD₃OD): 7.93 (s, 1H), 7.885 (d, J = 5.6 Hz, 1H), 7.331 (m, 1H), 7.204(m, 3H), 7.103 (t, J = 7.2 Hz, 1H), 6.958 (d, J = 7.6 Hz, 1H), 6.251 (s,1H), 6.176 (m, 1H), 3.603-3.572 (m, 4H), 3.068-3.041 (m, 2H), 2.454 (s,3H), (m, 2H), 2.197 (br, 2H), 1.783-1.750 (m, 2H), 1.563 (br, 2H), 1.477(m, 2H), 1.311-1.275 (m, 2H). MS (m/e): 475.4 (M + 1) 62N4-(4-fluoro-2-methyl-1H-indol-5-yl)- N2-(3-(3-(methylsulfonyl)propoxy)phenyl)pyrimidine- 2,4-diamine  

(DMSO-d₆): 7.932 (d, J = 6.0 Hz, 1H), 7.399 (s, 1H), 7.393 (d, J = 6.8Hz, 1H), 7.099 (m, 2H), 6.97 (m, 1H), 6.416 (d, J = 8.0 Hz, 1H), 6.207(s, 1H), 6.088 ( s, 1H), 3.84 (m, 2H), 3.196 (m, 2H), 3.010 ( s, 3H),2.400 (s, 3H), 2.014 (m, 2H). MS (m/e): 470.5 (M + 1). 632-(3-(4-(4-fluoro-2-methyl-1H-indol-5- ylamino)pyrimidin-2-ylamino)phenoxy)ethanol  

(DMSO-d₆): 7.938 (d, J = 6.0 Hz, 1H), 7.347 (m, 2H), 7.104 (m, 2H),6.950 (m, 1H), 6.410 (d, J = 8.0 Hz, 1H), 6.206 (s, 1H), 6.088 (s, 1H),3.788 (m, 2H), 3.630 (m, 2H), 2.401 (s, 3H). MS (m/e): 394.4 (M + 1). 64N4-(4-fluoro-2-methyl-1H-indol-5-yl)- N2-(3-(piperidin-3-yloxy)phenyl)pyrimidine-2,4-diamine  

(DMSO-d₆): 11.241 (s, 1H), 8.966 (s, 1H), 8.789 (s, 1H), 7.929 (d, J =5.6 Hz, 1H), 7.378 (s, 1H), 7.267 (d, J = 7.6 Hz, 1H), 7.120-7.053 (m,2H), 6.964 (m, 1H), 6.380 (d, J = 8.0 Hz, 1H) 6.207 (s, 1H), 6.010 (s,1H), 4.010 (s, 1H), 3.710 (m, 1H); 3.554 (s, 2H). 3.362 (m, 2H). 2.506(s, 3H) 2.401 (m, 2H) 1.234 (m, 2H), MS (m/e): 433.2 (M + 1) 65N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-((1-(methylsulfonyl)piperidin-4- yl)methoxy)phenyl)pyrimidine-2,4-diamine  

(CD₃OD): 8.021 (d, J = 5.6 Hz, 1H), 7.418 (s, 1H), 7.220-7.051 (m, 3H),6.998 (m, 1H), 6.612 (d, J = 7.4 Hz, 1H) 6.267 (s, 1H), 5.800 (d, J =5.6 Hz, 1H), 3.960 (d, J = 5.2 Hz, 2H), 3.810 (m, 2H); 3.362 (m, 2H).2.826 (s, 3H), 2.506 (s, 3H) 1.556 (m, 2H), 1.452 (m, 1H) 1.234 (m, 2H)66 1-(3-(4-(4-fluoro-2-methyl-1H-indol-5- yloxy)pyrimidin-2-ylamino)benzyl)piperidin-4-ol  

(CD₃OD): 8.247 (d, J = 5.6 Hz, 1H), 7.378 (s, 1H), 7.160-7.108 (m, 2H),6.956 (t, J = 8.0 Hz, 1H), 6.895-6.825 (m, 2H), 6.450 (d, J = 5.6 Hz,1H), 6.247 (s, 1H), 3.031 (s, 1H), 2.690-2.663 (m, 2H), 2.455 (s, 3H),2.069- 2.042 (m, 2H), 1.815- 1.716 (m, 2H), 1.562- 1.483 (m, 2H); MS(m/e): 448.5 (M + 1) 67 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(methylsulfonyl)phenyl)pyrimidin- 2-amine  

(CD₃OD): 8.292 (d, J = 5.6 Hz, 1H), 8.005 (s, 1H), 7.691 (d, J = 7.2 Hz,1H), 7.341 (d, J = 7.2 Hz, 1H), 7.102 (d, J = 8.8 Hz, 1H), 7.013 (t, J =1.2 Hz, 1H), 6.849 (t, J = 8.0Hz, 1H), 6.482 (d, J = 5.6 Hz, 1H), 6.221(s, 1H), 2.900 (s, 3H), 2.432 (s, 3H); MS (m/e): 413.4 (M + 1) 68N-cyclopropyl-2-(3-(4-(4-fluoro-2- methyl-lH-indol-5-yIoxy)pyrimidin-2ylamino)phenyl)acetamide  

(DMSO-d₆): 7.947 (m, 2H), 7.298 (m, 2H), 7.154 (d, J = 8.4 Hz, 1H),6.947 (m, 1H), 6.755 (m, 1H), 6.775 (d, J = 8.0 Hz, 1H), 6.441 (d, J =5.6 Hz, 1H), 6.240 (s, 1H), 3.027 (s, 2H ), 2.593 (m, 1H), 2.499 (s,3H), 0.596 (m, 2H), 0.390 (m, 2H ). MS (m/e): 432.5 (M + 1) 69(E)-3-(3-(4-(4-fluoro-2-methyl-lH-indol-5-yloxy)pyrimidin-2-yIamino)phenyl)-N- methylacrylamide  

(DMSO-d₆): 11.550 (s, 1H ), 9.791 (s, 1H), 8.385 (d, J = 5.2, 1H), 8.114(d, J = 4.8, 1H), 7.432 (d, J = 7.2, 2H), 7.214 (d, J = 10, 1H), 7.184(d, J = 3.2, 1H), 7.083 (d, J = 8, 2H), 6.942 (m, J = 16, 1H), 6.533 (d,J = 5.6, 1H, 6.402 (d, J = 15.6), 6.253 (s, 1H), 2.687 (d, J = 4.8, 3H),2.440 (s, 3H). MS (m/e): 418.2 (M + 1) 703-(3-(4-(4-fluoro-2-methyl-lH-indol-5-yloxy)pyrimidin-2-ylamino)phenyl)-N,N- dimethylpropanamide  

(DMSO-d₆): 11.397 (s, 1H), 9.420 (s, 1H), 8.334 (d, J = 5.6, 1H), 7.290(s, 1H), 7.241 (d, J = 7.2, 1H), 7.152 (d, J = 8.8, 1H), 6.919 (m, J =15.2, 1H), 6.803 (m, J = 15.6, 1H), 6.652 (d, J = 6.8, 1H), 6.451 (d, J= 5.6, 1H), 6.218 (s, 1H), 2.860 (s, 3H), 2.795 (s, 3H), 2.449 (m, J =14.8, 2H), 2.399 (s, 3H), 2.338 (m, J = 14.8, 2H). MS (m/e): 434.2(M + 1) 71 N-methyl-3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)benzamide  

MS (m/e): 372.4 (M) 72 N2-(2-fluorophenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

MS (m/e): 350.1 (M + 1) 73 3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzonitrile  

MS (m/e): 341.2 (M + 1) 74 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(methylthio)phenyl)pyrimidine-2,4- diamine  

MS (m/e): 362.3 (M + 1) 75 N,N-dimethyl-3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzenesulfonamide  

MS (m/e): 423.5 (M + 1) 76 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(morpholinosulfonyl)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 465.4 (M + 1) 77 N2-(3,4-dimethoxyphenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

MS (m/e): 376.3 (M + 1) 78 N2-(4-chlorophenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

MS (m/e): 350.3 (M + 1) 79 N2-(2,4-difluorophenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

MS (m/e): 352.2 (M + 1) 80 N2-(3-chloro-2-fluorophenyl)-N4-(2-methyl-1H-indoI-5-yl)pyrimidine-2,4- diamine  

MS (m/e): 368.3 (M + 1) 81 N2-(1H-indol-4-yl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

MS (m/e): 355.3 (M + 1) 82 N2-(4-(3-(dimethylamino)propoxy)phenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

MS (m/e): 417.4 (M + 1) 83 2-(4-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenoxy)ethanol  

MS (m/e): 376.3 (M + 1) 84 N2-(3-chloro-4-fluorophenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

MS (m/e): 368.3 (M + 1) 85 N2-(benzo[d][1,3]dioxol-5-yl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

MS (m/e): 360.3 (M + 1) 86 (1-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzyl)piperidin-4-yl)methanol  

MS (m/e): 443.4 (M + 1) 87 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(2-(4-(methylsulfonyl)piperazin-1- yl)ethoxy)phenyl)pyrimidine-2,4-diamine 

MS (m/e): 521.2 (M) 88 3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)-N- propylbenzenesulfonamide  

MS (m/e): 437.3 (M + 1) 89 N2-(2-chloro-4-fluorophenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

MS (m/e): 368.1 (M + 1) 90 2-chloro-4-fluoro-5-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenol  

MS (m/e): 384.3 (M + 1) 91 N2-(4-chloro-2-fluorophenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

MS (m/e): 368.3 (M + 1) 92 N2-(3-(2-(dimethylamino)ethoxy)phenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

MS (m/e): 403.4 (M + 1) 93 N2-(2-methyl-1H-indol-5-yl)-N4-(3-(3-(methylsulfonyl)propoxy)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 452.3 (M + 1) 94 2-(1-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzyl)piperidin-4- yl)ethanol  

MS (m/e): 457.4 (M + 1) 95 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(piperidin-4- ylmethoxy)phenyl)pyrimidine-2,4- diamine  

MS (m/e): 429.4 (M + 1) 96 N4-(2-methyl-1H-indol-5-y)-N2-(3-(piperidin-3-yloxy)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 416.4 (M + 1) 97 1-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzyl)piperidin-4-ol  

MS (m/e): 429.4 (M + 1) 98 (S)-N4-(2-methyl-1H-indol-5-yl)-N2-(3-(pyrrolidin-3-yloxy)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 401.4 (M + 1) 99 (S)-N4-(2-methyl-1H-indol-5-yl)-N2-(3-(1-(methylsulfonyl)pyrrolidin-3- yloxy)phenyl)pyrimidine-2,4-diamine  

MS (m/e): 479.5 (M + 1) 100 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(piperidin-4-yloxy)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 415.5 (M + 1) 101 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(3-(4-(methylsulfonyl)piperazin-1- yl)propoxy)phenyl)pyrimidine-2,4-diamine  

MS (m/e): 536.6 (M + 1) 102 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(3-morpholinopropoxy)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 459.6 (M + 1) 103 (R)-N4-(2-methyl-1H-indol-5-yl)-N2-(3-(1-(methylsulfonyl)pyrrolidin-3- yloxy)phenyl)pyrimidine-2,4-diamine  

MS (m/e): 479.5 (M + 1) 104 (E)-N,N-dimethyl-3-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)acrylamide  

MS (m/e): 413.2 (M + 1) 105 4-(4-fluoro-2-methyl-1H-indol-5-yl)-N-(3-(3-(thiomorpholino-l′,1′- dioxide)propoxy)phenyl)pyrimidin-2- amine  

MS (m/e): 507.5 (M + 1) 106 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(2-(methylamino)ethoxy)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 389.5 (M + 1) 107 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(3-(thiomorpholino-1′-oxide) propoxy)phenyl)pyrimidin-2-amine  

MS (m/e): 491.5 (M + 1) 108 N-(2-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenoxy)ethyl)methanesulfonamide  

MS (m/e): 453.4 (M + 1) 109 N4-(2-methyl-1H-indol-5-yl)-N2-(3.(3-thiomorpholinopropoxy) phenyl)pyrimidine-2,4-diamine 

MS (m/e): 475.5 (M + 1) 110 trifluoro-N-(4-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino) phenyl)methanesulfonamide  

MS (m/e): 463.4 (M + 1) 111 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(2-thiomorpholinoethoxy) phenyl)pyrimidine-2,4-diamine  

MS (m/e): 461.4 (M + 1) 112 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(2-pyrrolidinethoxy)phenyl)pyrimidine-2,4- diamine  

MS (m/e): 429.4 (M + 1) 113 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(2-morpholinoethylsulfonyl) phenyl)pyrimidine-2,4-diamine  

MS (m/e): 493.1 (M + 1) 114 N4-(2-methy1-1H-indol-5-yl)-N2-(3-(2-(pyrrolidin-1-yl) ethylsulfonyl)phenyl)pyrimidine-2,4- diamine  

MS (m/e): 477.1 (M + 1) 115 N4-(2-methyl-1H-indol-5-yl)-N2-(3-((4-(methylsulfonyl)piperazin-1- yl)methyl)phenyl)pyrimidine-2,4-diamine  

MS (m/e): 492.4 (M + 1) 116 2-(4-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzyl)piperazin-1-yl)ethanol  

MS (m/e): 458.5 (M + 1) 117 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(methylsulfonylmethyl)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 408.3 (M + 1) 118 N,N-dimethyl-3-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)propanamide  

MS (m/e): 415.5 (M + 1) 119 (E)-N-methyl-3-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)acrylamide  

MS (m/e): 399.2 (M + 1) 120 N4-(2-methyl-1H-indol-5-yl)-N2-(3-(tetrahydro-2H-pyran-4- yloxy)phenyl)pyrimidine-2,4-diamine  

MS (m/e): 416.4 (M + 1) 121 N2-(3-(2-aminoethoxy)phenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

MS (m/e): 375.3 (M + 1) 122 N-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino) benzyl)methanesulfonamide  

MS (m/e): 423.4 (M + 1) 123 N-(2-hydroxyethyl)-3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzamide  

MS (m/e): 403.2 (M + 1) 124 N-methyl-3-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)propanamide

MS (m/e): 401.2 (M + 1) 125 3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)-N-(2- (methylamino)-2-oxoethyl)benzamide  

MS (m/e): 430.2 (M + 1) 126 3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)-N-(2- morpholinoethyl)benzamide  

MS (m/e): 472.3 (M + 1) 127 3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)-N-(2- (piperidin-1-yl)ethyl)benzamide  

MS (m/e): 470.1 (M + 1) 128 trifluoro-N-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-yl amino)phenyl)methanesulfonamide  

MS (m/e): 463.0 (M + 1) 129 N-(2-methoxyethyl)-3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzamide  

MS (m/e): 417.2 (M + 1) 130 N-(4-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-yl amino)phenyl)methanesulfonamide  

MS (m/e): 409.1 (M + 1) 131 2-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)phenyl)-N- (2-morpholinoethyl)acetamide  

MS (m/e): 493.1 (M + 1) 132 N2-(6-methoxypyridin-3-yl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

MS (m/e): 347.4 (M + 1) 133 2-methyl-N-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)-1H-indol-5-amine  

MS (m/e): 370.3 (M + 1) 134 N-(3-(3-(dimethylamino)propoxy)phenyl)-4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- amine  

MS (m/e): 418.4 (M + 1) 135 2-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)phenoxy)ethanol  

MS (m/e): 377.4 (M + 1) 136 N-(3-(2-(dimethylamino)ethoxy)phenyl)-4-(2-methyl-1H-indol-5-yloxy)pyrimidin- 2-amine  

MS (m/e): 404.4 (M + 1) 137 N-cyclopropyl-2-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)phenyl)acetamide  

MS (m/e): 414.4 (M + 1) 138 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(3-(methylsulfonyl)propoxy)phenyl)pyrimidin- 2-amine  

MS (m/e): 453.4 (M + 1) 139 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(piperidin-4- ylmethoxy)phenyl)pyrimidin-2-amine  

MS (m/e): 448.2 (M + 1) 140 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(piperidin-3-yloxy)phenyl)pyrimidin-2- amine  

MS (m/e): 416.2 (M + 1) 141 4-(2-methyl-1H-indol-5-yloxy)-N-(3(piperidin-4-yloxy)phenyl)pyrimidin amine  

MS (m/e): 416.4 (M + 1) 142 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(1-(methylsulfonyl)piperidin-4- yloxy)phenyl)pyrimidin-2-amine  

MS (m/e): 494.5 (M + 1) 143 1-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)benzyl)piperidin-4-ol  

MS (m/e): 430.4 (M + 1) 144 (1-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)benzyl)piperidin-4-yl)methanol  

MS (m/e): 444.4 (M + 1) 145 2-(1-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)benzyl)piperidin-4-yl)ethanol  

MS (m/e): 458.5 (M + 1) 146 N-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)phenyl) methanesulfonamide  

MS (m/e): 409.12 (M + 1) 147 (S)-4-(2-methyl-1H-indol-5-yloxy)-N-(3-(1-(methylsulfonyl)pyrrolidin-3- yloxy)phenyl)pyrimidin-2-amine  

MS (m/e): 480.5 (M + 1) 148 (E)-N,N-dimethyl-3-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)phenyl)acrylamide  

MS (m/e): 415.5 (M + 1) 149 3-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)phenyl)-1- morpholinopropan-1-one  

MS (m/e): 158.5 (M + 1) 150 N-(3-(2-methoxyethoxy)phenyl)-4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- amine  

MS (m/e): 391.0 (M + 1) 151 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(morpholinosulfonyl)phenyl)pyrimidin-2- amine  

MS (m/e): 465.1 (M + 1) 152 N-(2-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)phenoxy)ethyl)methanesulfonamide  

MS (m/e): 454.2 (M + 1) 153 (R)-4-(2-methyl-1H-indol-5-yloxy)-N-(3-(1-(methylsulfonyl)pyrrolidin-3- yloxy)phenyl)pyrimidin-2-amine  

MS (m/e): 480.5 (M + 1) 154 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(2-morpholinoethoxy)phenyl)pyrimidin-2- amine  

MS (m/e): 446.4 (M + 1) 155 N-(2-(dimethylamino)ethyl)-3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)benzamide  

MS (m/e): 431.4 (M + 1) 156 N-(3-(2-methoxyethoxy)phenyl)-4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- amine  

MS (m/e): 391.3 (M + 1) 157 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(morpholinomethyl)phenyl)pyrimidin-2- amine  

MS (m/e): 416.4 (M + 1) 158 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(3-thiomorpholinopropoxy)phenyl)pyrimidin- 2-amine  

MS (m/e): 476.5 (M + 1) 159 N-(3-(2-(dimethylamino)ethylsulfonyl)phenyl)-4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- amine  

MS (m/e): 452.4 (M + 1) 160 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(2-morpholinoethylsulfonyl)phenyl)pyrimidin- 2-amine  

MS (m/e): 494.4 (M + 1) 161 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(2-(pyrrolidin-1-yl) ethylsulfonyl)phenyl)pyrimidin-2-amine  

MS (m/e): 478.4 (M + 1) 162 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(2-thiomorpholinoethoxy)phenyl)pyrimidin- 2-amine  

MS (m/e): 462.4 (M + 1) 163 4-(2-methyl-1H-indoI-5-yloxy)-N-(3-(2-(pyrrolidin-1- yl)ethoxy)phenyl)pyrimidin-2-amine  

MS (m/e): 430.3 (M + 1) 164 4-(2-methyl-1H-indol-5-yloxy)-N-(3-((4-(methylsulfonyl)piperazin-1- yl)methyl)phenyl)pyrimidin-2-amine  

MS (m/e): 493.5 (M + 1) 165 2-(4-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)benzyl)piperazin-1-yl)ethanol  

MS (m/e): 459.5 (M + 1) 166 4-(2-methyl-1H-indol-5-yloxy)-N-(3-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)pyrimidin-2-amine  

MS (m/e): 431.3 (M + 1) 167 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(methylsulfonylmethyl)phenyl)pyrimidin- 2-amine  

MS (m/e): 409.4 (M + 1) 168 tert-butyl 4-(2-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)phenoxy)ethyl)piperazine-1- carboxylate  

MS (m/e): 545.4 (M + 1) 169 N,N-dimethyl-3-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino))phenyl)propanamide  

MS (m/e): 416.5 (M + 1) 170 (E)-N-methyl-3-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)phenyl)acrylamide  

MS (m/e): 400.2 (M + 1) 171 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(tetrahydro-2H-pyran-4- yloxy)phenyl)pyrimidin-2- amine  

MS (m/e): 416.18 (M + 1) 172 N-(3-(2-aminoethoxy)phenyl)-4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- amine  

MS (m/e): 376.3 (M + 1) 173 N-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)benzyl)methanesulfonamide  

MS (m/e): 424.4 (M + 1) 174 N-(2-hydroxyethyl)-3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)benzamide  

MS (m/e): 404.1 (M + 1) 175 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(2-(piperazin-1-yl)ethoxy)phenyl)pyrimidin- 2-amine  

MS (m/e): 444.5 (M) 176 3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)-N-(2- (methylamino)-2-oxoethyl)benzamide  

MS (m/e): 431.2 (M + 1) 177 3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)-N-(2- morpholinoethyl)benzamide  

MS (m/e): 473.0 (M + 1) 178 3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)-N-(2- (piperidin-1-yl)ethyl)benzamide  

MS (m/e): 471.4 (M + 1) 179 N-methyl-3-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino))phenyl)propanamide  

MS (m/e): 402.2 (M + 1) 180 N-(2-methoxyethyl)-3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)benzamide  

MS (m/e): 418.1 (M + 1) 181 N-(4-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)phenyl)methanesulfonamide  

MS (m/e): 410.2 (M + 1) 182 2-(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)phenyl)-N-(2- morpholinoethyl)acetamide  

MS (m/e): 487.1 (M + 1) 183 4-(2-methyl-1H-indol-5-yloxy)-N-(3-(2-(methylsulfonyl)ethoxy)phenyl)pyrimidin- 2-amine  

MS (m/e): 439.2 (M + 1) 184 N-methyl(3-(4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)phenyl)methanesulfonamide  

MS (m/e): 424.4 (M + 1) 185 N-(6-methoxypyridin-3-yl)-4-(2-methyl-1H-indol-5-yloxy)pyrimidin-2- Amine  

MS (m/e): 348.2 (M + 1) 186 methyl 2-(4-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)acetate  

MS (m/e): 406.2 (M + 1) 187 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(2-methoxyphenyl)pyrimidine-2,4- diamine  

MS (m/e): 364.2 (M + 1) 188 N2-(3-bromophenyl)-N4-(4-fluoro-2-methyl-1H-indoI-5-yl)pyrimidine-2,4- diamine  

MS (m/e): 412.3 (M + 1) 189 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(methylsulfonyl) phenyl)pyrimidine-2,4-diamine  

MS (m/e): 412.3 (M + 1) 190 3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzonitrile  

MS (m/e): 359.3 (M + 1) 191 N2-(2-chloro-4-fluorophenyl)-N4-(4-fluoro-2-methyl-1H-indol-5- yl)pyrimidine-2,4-diamine  

MS (m/e): 386.2 (M + 1) 192 N-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)methanesulfonamide  

MS (m/e): 427.3 (M + 1) 193 N2-(3,4-difluorophenyl)-N4-(4-fluoro-2-methyl-1H-indol-5-yl)pyrimidine-2,4- diamine  

MS (m/e): 370.2 (M + 1) 194 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(2- morpholinoethoxy)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 463.4 (M + 1) 195 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)phenyl)pyrimidine-2,4-diamine  

MS (m/e): 540.3 (M + 1) 196 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(2-(2- morpholinoethoxy)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 462.3 (M) 197 N2-(3-(3- (dimethylamino)propoxy)phenyl)-N4-(4-fluoro-2-methyl-H-indol-5- yl)pyrimidine-2,4-diamine  

MS (m/e): 435.4 (M + 1) 198 N-cyclopropyl-2-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)acetamide  

MS (m/e): 431.4 (M + 1) 199 N-(2-(3-(4-(4-fluoro-2-methy-1H-indol-5-ylamino)pyrimidin-2-yl amino) phenoxy)ethyl)methanesulfonamide  

MS (m/e): 471.4 (M + 1) 200 2-(2-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenoxy)ethanol  

MS (m/e): 394.4 (M + 1) 201 N2-(3-(2-(dimethylamino)ethoxy)phenyl)-N4-(4- fluoro-2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine  

MS (m/e): 421.4 (M + 1) 202 (1-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzyl)piperidin-4-yl)methanol  

MS (m/e): 461.5 (M + 1) 203 3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)-N- methylbenzamide  

MS (m/e): 391.3 (M + 1) 204 trifluoro-N-(3-(4-(4-fluoro-2-melhyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)methanesulfonamide  

MS (m/e): 481.3 (M + 1) 205 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(piperidin-4- ylmethoxy)phenyl)pyrimidine-2,4- diamine  

MS (m/e): 446.22 (M + 1) 206 (E)-3-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)phenyl)- 1-morpholinoprop-2-en-1-one  

MS (m/e): 473.5 (M + 1) 207 trifluoro-N-(4-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenyl)methanesulfonamide  

MS (m/e): 481.3 (M + 1) 208 N-(5-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)pyridin-2- yl)acetamide  

MS (m/e): 394.4 (M + 1) 209 N4-(4-fluoro-2-methy-1H-indol-5-yl)-N2-(3-(morpholinosulfonyl) phenyl)pyrimidine-2,4- Diamine  

MS (m/e): 483.5 (M + 1) 210 3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)-N- methylbenzenesulfonamide  

MS (m/e): 427.1 (M + 1) 211 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(2- methoxyethoxy)phenyl)pyrimidine-2,4- diamine  

MS (m/e): 408.4 (M + 1) 212 4-(4-fluoro-2-methyl-1H-indol-5-yl)-N-(3-(3-(thiomorpholino-1′,1′- dioxide)propoxy)phenyl)pyrimidin-2- amine  

MS (m/e): 525.5 (M + 1) 213 N-(2-(dimethylamino)ethyl)-3-(4-(4-fluoro-2-methyl-1H-indol-5- ylamino)pyrimidin-2- ylamino)benzamide  

MS (m/e): 448.5 (M + 1) 214 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(2- (methylamino)ethoxy)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 407.5 (M + 1) 215 (E)-3-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)phenyl)- 1-morpholinoprop-2-en-1-one  

MS (m/e): 473.1 (M + 1) 216 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(3- thiomorpholinopropoxy)phenyl)pyrimidine- 2,4-diamine  

MS (m/e): 493.5 (M + 1) 217 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(2-morpholino ethylsulfonyl)phenyl)pyrimidine-2,4- diamine  

MS (m/e): 511.4 (M + 1) 218 N4-(4-fluoro.2-methyl-1H-indol-5-yl)-N2-(3-(2-thiomorpholino ethoxy)phenyl)pyrimidine-2,4- diamine  

MS (m/e): 479.4 (M + 1) 219 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(2-(pyrrolidin-1- yl)ethoxy)phenyl)pyrimidine-2,4- diamine  

MS (m/e): 447.4 (M + 1) 220 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-((4-(methylsulfonyl)piperazin-1- yl)methyl)phenyl)pyrimidine-2,4-diamine  

MS (m/e): 510.4 (M + 1) 221 2-(4-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzyl)piperazin-1- yl)ethanol  

MS (m/e): 474.7 (M − 1) 222 3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino) phenylmethanesulfonate  

MS (m/e): 428.4 (M + 1) 223 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(methylsulfonylmethyl) phenyl)pyrimidine-2,4- diamine  

MS (m/e): 426.4 (M + 1) 224 tert-butyl 4-(2-(3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-yl amino)phenoxy)ethyl)piperazine-1- carboxylate  

MS (m/e): 544.4 (M + 1) 225 tert-butyl 4-(2-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)phenoxy)ethyl)piperazine-1-carboxylate  

MS (m/e): 562.3 (M + 1) 226 3-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino))phenyl)- N,N-dimethylpropanamide  

MS (m/e): 433.4 (M + 1) 227 (E)-3-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)phenyl)- N-methylacrylamide  

MS (m/e): 417.2 (M + 1) 228 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)pyrimidine-2,4- diamine 

MS (m/e): 448.4 (M + 1) 229 N2-(3-(2-aminoethoxy)phenyl)-N4-(4-fluoro-2-methyl-1H-indol-5- yl)pyrimidine-2,4-diamine  

MS (m/e): 393.2 (M + 1) 230 N-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzyl)methanesulfonamide  

MS (m/e): 441.4 (M + 1) 231 3-(4-(4-fluoro-2-methyl-1H-indoI-5-ylamino)pyrimidin-2-ylamino)-N-(2- hydroxyethyl)benzamide  

MS (m/e): 421.2 (M + 1) 232 3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)-N-(2- morpholinoethyl)benzamide  

MS (m/e): 490.1 (M + 1) 233 3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)-N-(2- (piperidin-1- yl)ethyl)benzamide  

MS (m/e): 488.4 (M + 1) 234 3-(3-(4-(4-fluoro-2-mcthyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)phenyl)-N methylpropanamide  

MS (m/e): 419.2 (M + 1) 235 3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)-N-(2- methoxyethyl)benzamide  

MS (m/e): 435.2 (M + 1) 236 N-(4-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-yl amino)phenyl)methanesulfonamide  

MS (m/e): 427.2 (M + 1) 237 2-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)phenyl)-N- (2-morpholinoethyl)acetamide  

MS (m/e): 504.1 (M + 1) 238 3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)-N-(2- (methylamino)-2- oxoethyl)benzamide  

MS (m/e): 448.2 (M + 1) 239 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(tetrahydro-2H-pyran-4- yloxy)phenyl)pyrimidine-2,4- diamine  

MS (m/e): 434.4 (M + 1) 240 1-(3-(4-(4-fluoro-2-methyl-1H-indol-5-ylamino)pyrimidin-2- ylamino)benzyl)sulphonyl- methylamine  

MS (m/e): 441.4 (M + 1) 241 N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(6-methoxypyridin-3-yl)pyrimidine- 2,4-diamine  

MS (m/e): 365.4 (M + 1) 242 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(2-morpholinoethoxy) phenyl)pyrimidin-2-amine  

MS (m/e): 464.4 (M + 1) 243 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(3-morpholino propoxy)phenyl)pyrimidin-2-amine  

MS (m/e): 478.4 (M + 1) 244 2-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)phenoxy)ethanol  

MS (m/e): 395.4 (M + 1) 245 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(3-(thiomorpholino-l′,1′-dioxide) propoxy)phenyl)pyrimidin-2-amine 

MS (m/e): 526.7 (M + 1) 246 (R)-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(pyrrolidin-3- yloxy)phenyl)pyrimidin-2-amine  

MS (m/e): 420.5 (M + 1) 247 (S)-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(pyrrolidin-3- yloxy)phenyl)pyrimidin-2-amine  

MS (m/e): 420.5 (M + 1) 248 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(1-(methylsulfonyl)piperidin-4- yloxy)phenyl)pyrimidin-2-amine  

MS (m/e): 512.4 (M + 1) 249 (R)-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(1- (methylsulfonyl)pyrrolidin-3-yloxy)phenyl)pyrimidin-2-amine  

MS (m/e): 498.4 (M + 1) 250 N-(2-(dimethylamino)ethyl)-3-(4-(4-fluoro-2-methyl-1H-indol-5- yloxy)pyrimidin-2- ylamino)benzamide

MS (m/e): 448.5 (M + 1) 251 (1-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)benzyl)piperidin-4- yl)methanol  

MS (m/e): 462.4 (M + 1) 252 2-(1-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)benzyl)piperidin-4- yl)ethanol  

MS (m/e): 476.5 (M + 1) 253 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(2-(methylamino)ethoxy) phenyl)pyrimidin-2-amine  

MS (m/e): 408.4 (M + 1) 254 (E)-3-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)phenyl)-1- morpholinoprop-2-en-1-one  

MS (m/e): 474.5 (M + 1) 255 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(morpholino methyl)phenyl)pyrimidin-2-amine  

MS (m/e): 434.5 (M + 1) 256 (S)-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(1- (methylsulfonyl)pyrrolidin-3-yloxy)phenyl)pyrimidin-2-amine  

MS (m/e): 498.4 (M + 1) 257 3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)-N- methylbenzamide  

MS (m/e): 392.4 (M + 1) 258 N-(2-(3-(4-(4-fIuoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)phenoxy) ethyl)methanesulfonamide  

MS (m/e): 472.4 (M + 1) 259 trifluoro-N-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl amino) phenyl)methanesulfonamide  

MS (m/e): 482.3 (M + 1) 260 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(3-thiomorpholinopropoxy) phenyl)pyrimidin-2-amine  

MS (m/e): 494.5 (M + 1) 261 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(2-(pyrrolidin-1-yl)ethylsulfonyl) phenyl)pyrimidin-2-amine  

MS (m/e): 496.4 (M + 1) 262 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(2-morpholinoethylsulfonyl) phenyl)pyrimidin-2-amine  

MS (m/e): 512.4 (M + 1) 263 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(2-thiomorpholinoethoxy) phenyl)pyrimidin-2-amine  

MS (m/e): 480.4 (M + 1) 264 4-(4-flucro-2-methyl-1H-indol-5-yloxy)-N-(3-(2-(pyrrolidin-l- yl)ethoxy)phenyl)pyrimidin-2-amine  

MS (m/e): 448.4 (M + 1) 265 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-((4-(methylsulfonyl)piperazin-1- yl)methyl)phenyl)pyrimidin-2-amine 

MS (m/e): 511.4 (M + 1) 266 2-(4-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)benzyl) piperazin-1-yl)ethanol  

MS (m/e): 477.5 (M + 1) 267 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-3-((tetrahydro-2H-pyran-4-yl)methoxy) phenyl) pyrimidin-2-amine  

MS (m/e): 449.4 (M + 1) 268 trifluoro-N-(4-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy) pyrimidin-2-ylamino) phenyl)methanesulfonamide  

MS (m/e): 482.3 (M + 1) 269 tert-butyl 4-(2-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2- ylamino)phenoxy)ethyl)piperazine-1-carboxylate  

MS (m/e): 563.4 (M + 1) 270 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(tetrahydro-2H-pyran-4- yloxy)phenyl)pyrimidin-2-amine  

MS (m/e): 435.4 (M + 1) 271 N-(3-(2-aminoethoxy)phenyl)-4-(4-fluoro-2-methyl-1H-indol-5- yloxy)pyrimidin-2-amine  

MS (m/e): 394.4 (M + 1) 272 N-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl amino)benzyl)methanesulfonamide  

MS (m/e): 442.4 (M + 1) 273 3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)-N-(2- hydroxyethyl)benzamide  

MS (m/e): 422.1 (M + 1) 274 3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)-N-(2- (methylamino)-2- oxoethyl)benzamide  

MS (m/e): 449.5 (M + 1) 275 3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)-N-(2- morpholinoethyl)benzamide  

MS (m/e): 491.1 (M + 1) 276 N-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl amino) phenyl)methanesulfonamide  

MS (m/e): 428.1 (M + 1) 277 3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)-N-(2- (piperidin-1- yl)ethyl)benzamide  

MS (m/e): 489.1 (M + 1) 278 3-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)phenyl)-N- methylpropanamide  

MS (m/e): 420.2 (M + 1) 279 3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)-N-(2- methoxyethyl)benzamide  

MS (m/e): 436.1 (M + 1) 280 N-(4-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl amino) phenyl)methanesulfonamide  

MS (m/e): 428.1 (M + 1) 281 2-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-ylamino)phenyl)-N-(2- morpholinoethyl)acetamide  

MS (m/e): 505.1 (M + 1) 282 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(3-(2-(methylsulfonyl) ethoxy)phenyl)pyrimidin-2-amine  

MS (m/e): 457.2 (M + 1) 283 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-N-(6-methoxypyridin-3-yl)pyrimidin-2- amine  

MS (m/e): 366.4 (M + 1)

EXAMPLE 284 Synthesis of3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)phenol (Compound284)

A solution ofN2-(3-methoxylphenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine(0.1mmol) in 5 ml CH₂Cl₂ was placed in an ice bath. To this was addedBBr₃(0.5 mmol). The reaction mixture was stirred overnight at roomtemperature, then poured into ice water, and extracted with ethylacetate. The organic layer was washed sequentially with water and brine,dried over anhydrous Na₂SO₄, and concentrated. The residue was purifiedby column chromatography to provide the desired product in a yield of83%.

¹H NMR (DMSO-d₆, 400 MHz): δ 10.501 (s, 1H), 9.115 (s, 1H), 8.956 (s,1H), 8.868 (s, 1H), 7.908 (d, J=6 Hz, 1H), 7.716 (s,1H), 7.271 (d, J=8Hz, 1H), 7.210 (d, J=8.4 Hz, 1H), 7.114. (d, J=8 Hz, 1H), 6.968 (t, J=8Hz, 1H), 6.322 (dd, J=8, 1.6 Hz, 1H), 6.097 (m, 2H), 2.377 (s, 3H); MS(m/e): 331.4 (M+1).

EXAMPLES 285-295 Syntheses of Compounds 285-295

Compounds 285-295 were each synthesized in a manner similar to thatdescribed in Example 284.

compound Name ¹H NMR (CD₃OD, 400 MHz)/MS 285

7.863 (d, J = 6.0 Hz, 1H), 7.286 (d, J = 8.8 Hz, 1H), 6.830 (br, 2H),6.125-6.080(m, 4H), 5.558-5.527 (m, 2H), 2.415(s, 3H); MS(m/e): 411.8(M + 1). 286

7.791( d, J = 6.0 Hz, 2H), 7.584(s, 1H), 7.047(d, J = 8.8 Hz, 1H), 7.063(d, J = 7.6 Hz, 1H), 6.974(t, J = 7.6 Hz, 1H), 6.882(d, J = 8.0 Hz, 1H),6.794(t, J = 8.0 Hz, 1H), 6.164(d, J = 6.0 Hz, 1H), 6.124(s, 1H), 2.027(s, 3H); MS(m/e): 332.2 (M + 1). 287

10.573(s, 1H), 9.162(s, 1H), 9.007(s, 1H), 8.985(s, 1H), 7.952(d, J =5.6 Hz, 1H), 7.766(s, 1H), 7.301(d, J = 8 Hz, 1H), 7.262(d, J = 8 Hz,1H), 7.123(d, J = 8 Hz, 1H), 7.011(m, 1H), 6.332(dd, J = 8, 1.6 Hz, 1H),6.103 (m, 2H), 2.391(s, 3H); MS(m/e): 331.4 (M + 1) 289

8.133( d, J = 6.0 Hz, 1H), 7.324( d, J = 8.4 Hz, 1H), 7.225-7.183(m,3H), 6.819 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.533 (s, 1H), 6.530 (s,1H), 6.213 (d, J = 5.6 Hz, 1H), 6.172 (s, 1H), 2.428 (s, 3H); MS(m/e):374.3 (M + 1). 290

8.179( d, J = 6.0 Hz, 1H), 7.333( d, J = 8.8 Hz, 1H), 7.193(s, 1H),7.095(s, 1H), 6.953( d, J = 7.2 Hz, 1H), 6.902( t, J = 8.0 Hz, 1H),6.831( d, J = 8.8 Hz, 1H), 6.387( d, J = 7.6 Hz, 1H), 6.244( d, J = 6.0Hz, 1H), 6.171 (s, 1H), 3.332 (s, 3H), 2.454 (s, 3H); MS(m/e): 333.2(M + 1). 291

11.249(s, 1H), 8.943 (d, J = 4.8 Hz, 1H), 7.920 (d, J = 5.6 Hz, 1H),7.867 (m, J = 6.4 Hz, 2H), 7.128(d, J = 8.0 Hz, 1H), 7.078(t, J =8.4-6.8 Hz, 1H), 6.797(s, 2H), 6.589 (s, 1H), 6.217(s, 1H), 6.075(s,1H), 4.061(m, J = 7.2-6.8 Hz, 1H) 2.406(s, 3H); MS: 350.2 (M + 1). 292

11.212(s, 1H), 8.845(s, 1H), 8.689(d, J = 10.0 Hz, 1H), 7.868 (d, J =5.6 Hz, 2H), 7.427(d, J = 8.4 Hz, 2H), 7.107(t, J = 8.4-6.4 Hz, 1H),6.509(d, J = 8.0 Hz, 2H), 6.208 (s, 1H), 5.940(m, J = 3.6-1.6 Hz, 1H),4.060(m, J = 7.2-6.8 Hz, 1H), 2.408 (s, 3H); MS(m/e): 350.2 (M + 1). 293

11.217(s, 1H), 9.069(s, 1H), 8.836(s, 1H), 8.715(s, 1H), 7.922(d, J =6.0 Hz, 1H), 7.224(d, J = 8.4 Hz, 2H), 7.128(T, J = 6.4-2.4 Hz, 2H),6.839(t, J = 8.4-6.4 Hz, 1H), 6.268(d, J = 1.6 Hz, 2H), 6.249 (s, 1H),6.207 (s, 1H), 4.043(m, J = 7.2-6.8 Hz, 1H), 2.400 (s, 3H); MS(m/e):350.2 (M + 1). 294

9.500 (s, 1H), 9.175 (s, 1H), 9.054 (s, 1H), 8.164 (s, 1H), 8.003 (d, J= 6.0 Hz, 1H), 7.569 (m, 2H), 7.230 (m, 2H), 6.996 (dd, 1H), 6.338 (d, J= 8.0 Hz, 1H), 7.239 (d, J = 6.0 Hz, 1H), 2.607 (s, 3H). MS(m/e): 334.2(M + 1). 295

MS (m/e): 351.4 (M + 1)

EXAMPLE 296 Synthesis ofN-(2-methoxypyrimidin-4-yl)-N-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine(Compound 296)

The solution of 2-chloropyrimidin-4-amine (1 mmol) and sodium methoxide(1.5 mmol) in 10 ml methanol was refluxed for 2 h, after removing ofsolvent, the residue was dissolved in CH₂Cl₂ and washed with water,dried over anhydrous NaSO4, concentrated in vacuo to give2-methoxypyrimidin-4-amine.

To a solution of 2-methoxypyrimidin-4-amine (0.1 mmol) andN-(2-chloropyrimidin-4-yl)-2-methyl-1H-indol-5-amine (0.1 mmol) in 3 mldioxide, CsCO₃ (0.2 mmol), Pd(OAc)₂ (10 mmol %) and Xantphos (10 mmol %)were added. The mixture was stirred under microwave irradiation at 200°C. for 40 mins. After cooling the solution was filtered and the filtratewas concentrated in vacuo, the residue was purified by columnchromatography (C-18) to giveN-(2-methoxypyrimidin-4-yl)-N-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine(yield 48%).

¹H NMR(DMSO-d6, 400 MHz): 10.839 (s, 1H), 9.718 (s, 1H), 9.281 (s, 1H),8.162 (d, J=6.0 Hz, 1H), 8.032 (m, 2H), 7.693 (s, 1H), 7.251 (d, J=8.8Hz, 1H), 7.099 (d, J=7.2 Hz, 1H), 6.300 (d, J=6.0 Hz, 1H), 6.107 (s,1H), 3.863 (s, 3H), 2.383 (s, 3H); MS (m/e): 348.2 (M+1)

EXAMPLES 297-299 Syntheses of Compounds 297-299

Compounds 297-299 were each synthesized in a manner similar to thatdescribed in Example 296.

compound Name ¹H NMR (DMSO-d₆, 400 MHz)/MS 297

10.837(s, 1 H), 9.421 (s, 1 H), 9.144 (s, 1 H), 7.978 (d, J = 6.0 Hz,1H), 7.838(d, J = 6.0 Hz, 1H), 7.606 (s, 1H), 7.333-7.303 (m, 2H),7.249(d, J = 8.4 Hz, 1H), 7.084 (d, J = 8.0 Hz, 1H), 6.205 (d, J = 5.6Hz, 1H), 6.088 (s, 1H), 3.775 (s, 3H), 2.382 (s, 3H); MS (m/e): 347.2(M + 1) 298

11.258 (s, 1 H), 10.400 (br, 1 H), 9.036 (s, 1 H), 8.829 (s, 1 H), 8.509(s, 1 H), 8.048 (d, J = 8.4 Hz, 1H), 7.911 (d, J = 5.6 Hz, 1H),7.007-7.122 (m, 2H), 6.743 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.194 (s, 1H),6.012 (br, 1H), 3.166 (s, 3H), 2.397 (s, 3H); MS (m/e): 428.1 (M + 1)299

MS(m/e): 411.4 (M + 1)

EXAMPLE 300 Synthesis ofN-(2-(4-fluorophenoxy)pyrimidin-4-yl)-2-methyl-1H-indol-5-amine(Compound 300)

N-(2-chloropyrimidin-4-yl)-2-methyl-1H-indol-5-amine (0.1 mmol) andp-fluorophenol (0.1 mmol) were dissolved in 0.5 ml DMF. To this wasadded K₂CO₃ (0.2 mmol). After stirred at 60° C. for 5 h, the reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water and brine sequentially, dried byanhydrous Na₂SO₄, and concentrated. The resulting oil residue waspurified by column chromatography to provide compound 300 in a yield of76%.

¹H NMR (DMSO-d6, 400 MHz): δ 10.802 (s, 1H), 9.491 (s, 1H), 7.990 (d,J=5.4 Hz 1H), 7.495 (s, 1H), 7.295 (m, J=8.4-3.6 Hz, 4H), 7.236 (d,J=5.4 Hz 1H), 7.133 (d, J=5.6 Hz, 1H), 6.486 (d, J=5.6 Hz, 1H), 5.902(s, 1H), 2.402 (s, 3H); MS (m/e): 335.1 (M+1).

EXAMPLE 301-303 Syntheses of Compounds 301-303

Compounds 301-303 were prepared in a similar manner to that described inExample 300.

Compound Name ¹H NMR (CD₃OD, 400 MHz)/MS 301

11.190 (s, 1H), 9.046 (s, 1H), 7.959(s, 1H), 7.931 (d, J = 6.0 Hz, 1H),7.681 (d, J = 7.2 Hz, 2H), 7.361(t, J = 8.0-7.6 Hz, 2H), 7.114 (m, J =8.4-7.2 Hz, 3H), 6.903 (d, J = 8.0 Hz, 2H), 6.755 (d, J = 7.2 Hz, 2H),6.179 (s, 1H), 6.024 (s, 1H), 2.338 (s, 3H); MS(m/e): 409.2 (M + 1) 302

7.739 (d, J = 6.4Hz, 1H), 7.593 (s, 1H), 7.252 (d, J = 7.6 Hz, 1H),7.119 (d, J = 8.0 Hz, 1H), 6.009 (s, 1H), 6.016 (d, J = 6.0 Hz, 1H),2.425(s, 3H), 0.784 (m, J = 5.2-2.4, 2H), 0.626 (m, J = 2.0-0.8 Hz, 3H),0.547 (m, J = 2.0-1.2 Hz, 3H). MS(m/e): 280.2 (M + 1) 303

MS (m/e): 322.3 (M + 1)

EXAMPLE 304 Synthesis of5-(2-(3-methoxyphenoxy)pyrimidin-4-yloxy)-2-methyl-1H-indole (Compound304)

To a solution of 2,4-dichloropyrimidine (1 mmol) and5-hydroxy-2-methylindole (1 mmol) in 5 ml EtOH was added Et₃N (1 mmol).The reaction mixture was refluxed for 5 h. After removal of the solventin vacuo and addition of H₂O, the mixture was extracted with EtOAc. Theorganic layers were combined, washed with a saturated NaCl aqueoussolution, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresulting oil residue was purified by column chromatography to give5-(2-chloropyrimidin-4-yloxy)-2-methyl-1H-indole in a yield of 75%.

5(2-Chloropyrimidin-4-yloxy)-2-methyl-1H-indole (0.1 mmol) andm-methoxyphenol (0.1 mmol) were dissolved in 0.5 ml DMF. K₂CO₃ (0.2mmol) was then added. After the reaction mixture was stirred at 60° C.for 5 h, it was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water and brine sequentially, dried overanhydrous Na₂SO₄, and concentrated. The crude product was purified bycolumn chromatography to provide compound 304 in a yield of 76%.

¹H NMR (CD₃OD, 400 MHz): δ 8.303 (d, J=5.6 Hz, 1H), 8.084 (s, 1H),7.305-7.262 (m, 3H), 6.908 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 6.816-6.764 (m,3H), 6.463 (d, J=5.6 Hz, 1H), 6.226 (s, 1H), 3.780 (s, 3H), 2.465 (s,3H); MS (m/e): 346.5 (M-1).

EXAMPLE 305 Synthesis of3-(4-(2-methyl-1H-indol-5-ylamino)pyrimidin-2-ylamino)benzonitrile(Compound 305)

To a solution of 2,4-dichloropyrimidine (1 mmol) and5-Aminobenzimidazole (1 mmol) in 5 ml EtOH, was added Et₃N (1 mmol). Thereaction mixture was refluxed for 5 hours. After removal of the solventin vacuo and addition of H₂O, the mixture was extracted with EtOAc. Theorganic layers were combined, washed with a saturated NaCl aqueoussolution, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was purified by column chromatography to giveN-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine in a yield of80%.

N-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine (0.1 mmol),3-aminobenzonitrile (0.1 mmol), and p-TsOH monohydrate (0.2 mmol) weredissolved in 0.5 ml DMF. After the reaction mixture was stirred at 60°C. for 5 h, it was diluted with water and extracted with ethyl acetate.The organic layer was washed with water and brine sequentially, driedover anhydrous Na₂SO₄, and concentrated. The resulted oil was purifiedby column chromatography to provide compound 305 in a yield of 76%.

¹H NMR (CD₃OD, 400 MHz): δ 8.178 (s, 1H), 7.942 (d, J=6.4 Hz,2H), 7.825(br, 1H), 7.633-7.603 (m, 2H), 7.469 (dd, J=8.8 Hz, 5 Hz, 1H), 7.212 (t,J=8.4 Hz, 1H), 7.075 (d, J=8.0 Hz, 1H), 6.254 (d, J=6.0 Hz,1H), 3.345(s, 1H); MS: 327.2 (M+1).

EXAMPLE 306 Synthesis ofN2-(3-methoxyphenyl)-N4-(2-methylbenzo[d]oxazol-6-yl)pyrimidine-2,4-diamine(Compound 306)

To a solution of 2,4-dichloropyrimidine (1 mmol) and2-methyl-1,3-benzoxazol-5-amine (1 mmol) in 5 ml EtOH was added Et₃N (1mmol). The reaction mixture was refluxed for 5 h. After removal of thesolvent in vacuo and addition of H₂O, the mixture was extracted withEtOAc. The organic layers were combined, washed with a saturated NaClaqueous solution, dried over anhydrous Na₂SO₄, and concentrated invacuo. The residue was purified by column chromatography to giveN-(2-chloro pyrimidin-4-yl)-2-methylbenzo[d]oxazol-6-amine in a yield of73%.

N-(2-chloropyrimidin-4-yl)-2-methylbenzo[d]oxazol-6-amine (0.1 mmol),3-methoxyaniline (0.1 mmol), and p-TsOH monohydrate (0.2 mmol) weredissolved in 0.5 ml DMF. After the reaction mixture was stirred at 60°C. for 5 h, it was diluted with water and extracted with ethyl acetate.The organic layer was washed with water and brine sequentially, driedover anhydrous Na₂SO₄, and concentrated. The resulting oil residue waspurified by column chromatography to provide compound 306 in a yield of82%.

¹H NMR (DMSO-d6, 400 MHz): δ 9.431 (s, 1H), 9.158 (s, 1H), 8.136 (s,1H), 8.022 (d, J=5.6 Hz,1H), 7.566 (d, J=8.8 Hz, 1H), 7.517 (d, J=8.8Hz, 1H), 7.418 (s, 1H), 7.367 (d, J=8.0 Hz 1H), 7.126 (t, J=8.4 Hz, 1H),6.490 (m, 1H), 6.224 (d, J=5.2 Hz,1H), 3.674 (s, 3H), 2.609 (s, 3H); MS(m/e): 348.3 (M+1).

EXAMPLE 307 Synthesis ofN2-(3-ethynylphenyl)-N4-(2-methylbenzo[d]oxazol-6-yl)pyrimidine-2,4-diamine(Compound 307)

Compound 307 was synthesized in a similar manner to that described inExample 306.

¹H NMR (DMSO-d6, 400 MHz): δ 9.566 (d, J=5.2 Hz, 1H), 9.309 (s, 1H),8.099 (s, 1H), 8.038 (d, J=6.0 Hz, 1H), 7.917 (s, 1H), 7.805 (d, J=8.4Hz, 1H), 7.574 (m, 2H), 7.231 (m, 1H), 6.996 (d, J=7.6 Hz, 1H), 7.278(d, J=5.6 Hz,1H), 4.059 (s, 1H), 2.608 (s, 3H); MS (m/e): 342.2 (M+1).

EXAMPLE 308 Synthesis ofN2-(3-ethynylphenyl)-N4-(1H-indazol-6-yl)pyrimidine-2,4-diamine(Compound 308)

To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-aminoindazole (1mmol) dissolved in 5 ml EtOH was added Et₃N (1 mmol). The reactionmixture was refluxed for 5 h. After removal of the solvent in vacuo andaddition of H₂O, the mixture was extracted with EtOAc. The organiclayers were combined, washed with a saturated NaCl aqueous solution,dried over anhydrous Na₂SO4, and concentrated in vacuo. The resulted oilwas purified by column chromatography to giveN-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine in a yield of 80%.

N-(2-chloropyrimidin-4-yl)-1H-indazol-5-amine (0.1 mmol),3-ethnylaniline (0.1 mmol), and p-TsOH (0.2 mmol, monohydrate) weredissolved in 0.5 ml DMF. After the reaction mixture was stirred at 60°C. for 5 h, it was diluted with water and extracted with ethyl acetate.The organic layer was washed with water and brine sequentially, driedover anhydrous Na₂SO₄, and concentrated. The residue was purified bycolumn chromatography to provide compound 308 in a yield of 74%.

¹H NMR (DMSO-d₆, 400 MHz): δ 12.966 (brs, 1H), 9.344 (brs, 1H), 9.234(brs, 1H), 8.145 (s, 1H), 8.005 (m, 2H), 7.893 (s, 1H), 7.795 (d, 1H),7.527 (d, J=8.8 Hz, 1H), 7.471 (d, J=8.8 Hz, 1H), 7.212 (t, 1H), 7.021(d, 1H), 6.626 (d, 1H), 4.037 (s, 1H); MS (m/e): 327.2 (M+1).

EXAMPLE 309 Synthesis ofN2-(3-methoxylphenyl)-N4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine(Compound 309)

2,4-Dichloro-5-fluoropyrimidine (1 mmol) and 5-amino-2-methylindole (1.5mmol) were dissolved in 3 ml CH₃OH and 9 ml H₂O. After the reactionmixture was stirred at room temperature for 1 h, it was diluted withH₂O, acidified with 2N HCl, and sonicated. The reaction mixture was thenfiltered, washed with H₂O and dried to giveN-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-1H-indol-5-amine in a yieldof 78%.

N-(2-chloro-5-fluoropyrimidin-4-yl)-2-methyl-1H-indol-5-amine (0.1mmol), m-methoxyaniline (0.1 mmol), p-TsOH monohydrate (0.2 mmol) weredissolved in 0.5 ml DMF. After the reaction mixture was stirred at 60°C. for 5 h, it was diluted with water and extracted with ethyl acetate.The organic layer was washed with water and brine sequentially, driedover anhydrous Na₂SO₄, and concentrated. The residue was purified bycolumn chromatography to provide compound 309 in a yield of 60%.

¹H NMR (CD₃OD, 400 MHz, δ ppm): 7.854 (d, J=4.0 Hz, 1H), 7.703 (d, J=1.6, 1H), 7.248 (s, 2H), 7.177 (br, 2H), 7.054 (t, J=4.2 Hz, 2H), 6.942(s, 2H), 3.506 (s, 3H), 2.235 (s, 3H); MS (m/e): 364.2 (M+1).

EXAMPLE 310 Synthesis of2-(3-methoxyphenylamino)-4-(2-methyl-1H-indo1-5-ylamino)pyrimidine-5-carbonitrile(Compound 310)

2-Methyl-2-thiopseudourea (5 mmol) and ethyl ethoxymethylenecyanoacetate(5 mmol) were dissolved in 20 ml EtOH. To this was added K₂CO₃ (10mmol). After the mixture was refluxed for 48 h, it was cooled to roomtemperature and filtered. The solvent was concentrated in vacuo andpurified by column chromatography to give4-hydroxy-2-(methylthio)pyrimidine-5-carbonitrile in a yield of 65%.

4-Hydroxy-2-(methylthio)pyrimidine-5-carbonitrile (3 mmol) andm-anisidine (3 mmol) in pentan-1-ol was refluxed for 40 h undernitrogen. The reaction mixture was concentrated in vacuo. The residuewas washed with water and dried to afford4-hydroxy-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile.

To a solution of4-hydroxy-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile in POCl₃ wasadded DMF 0.5 ml. The solution was refluxed for 3 h. The reactionmixture was cooled to room temperature and poured into ice-water. Thesolution was adjusted to pH=8-9 by aqueous sodium carbonate solution andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, concentrated in vacuo to afford4-chloro-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile.

4-Chloro-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile was convertedto compound 310 in a similar manner to that described in Example 1.

¹H NMR (DMSO-d6, 400 MHz): δ 10.925(s, 1H), 9.710 (d, J=11.2 Hz, 1H),9.349 (d, J=10.4 Hz,1H), 8.441 (s, 1H), 7.474 (s, 1H), 7.252 (s, 1H),7.223 (d, J=6.8 Hz, 1H), 7.187 (s, 1H), 7.062 (m, J=1H), 6.923 (d, J=2.0Hz, 1H), 6.485 (t, 1H); 6.098 (s, 1H), 3.453 (s, 3H), 2.387 (s, 3H); MS(m/e): 371.2 (M+1).

EXAMPLE 311-317 Syntheses of Compounds 311-317

Compounds 311-317 were prepared in a similar manner to that described inExample 310.

compound Name/Structure ¹HNMR(DMSO-d₆, 400 Hz)/MS 311

11.184 (s, 1H), 10.745 (s, 1H), 9.492 (s, 1H), 8.396 (s, 1H), 7.322 (s,1H), 7.292 (d, J = 7.2, 1H), 7.147 (m, 1H), 6.919 (m, 1H), 6.815 (d, J =8.8, 1H), 6.416 (d, J = 7.2, 1H), 6.261 (t, J = 4.8, 1H), 6.129 (s, 1H),3.447 (m, 2H), 3.547 (m, 4H), 2.398 (s, 3H), 2.337 (m, 6H), 1.747 (m,2H). MS (m/e): 484.2 (M + 1) 312

MS (m/e): 485.3 (M + 1) 313

MS (m/e): 470.5 (M + 1) 314

MS (m/e): 427.2 (M + 1) 315

MS (m/e): 401.4 (M + 1) 316

MS (m/e): 488.5 (M + 1) 317

MS (m/e): 391.1 (M + 1)

EXAMPLE 318 KDR Kinase Activity Assay Using Z′-Lyte Kinase Assay Kit

Inhibition of kinase activity of a recombinant KDR catalytic domain(Invitrogen, Carlsbad, Calif., U.S.A., Cat. PV3660) was determined usingZ′-LYTE™ Tyr1 Peptide assay kit (Invitrogen, Cat. PV3190) in a black384-well plate (Thermo labsystems, Cambridge, U.K., Cat. 7805). Theassay was performed according to the procedures recommended by themanufacturer.

Briefly, a test compound (10 mM stock in DMSO) was diluted to 1:4 withdistilled water containing 8% DMSO. The solution was placed in a testwell and three control wells (C1, C2, and C3) at 2.5 μl/well.Coumarin-fluorescein double-labeled peptide substrate was mixed with theKDR catalytic domain (“kinase”). 5 μl of the kinase/peptide mixture wasadded to each of the test, C1, and C2 wells, but not C3 (Finalconcentration: 0.3 μg/ml of Kinase, 2 μM of peptide). 5 μl ofPhosphor-Tyr1 peptide was added to the C3 well. 2.5 μl of 40 μM ATP wasadded to the test well and C2 well and 2.5 μl of 1.33× kinase buffer (1×buffer: 50 mM HEPES, pH 7.5, 0.01% Brij-35, 5 mM MgCl₂, 5 mM MnCl₂, and1 mM EGTA) was added to the C1 and C3 wells. The plate was briefly spunat 1000 rpm to settle all solution down to the bottom of the wells andthen sealed and shaken at 250 rpm and 25° C. for 1 hour.

A development reagent was diluted to 1:128 according to therecommendation of the manufacturer. 5 μl of the diluted developmentreagent was added to each well. The plate was spun at 1000 rpm to settleall solution down to the wells, and then sealed and shaken at 250 rpmand 25° C. for 1 hour.

5 μl of a stop reagent was added to each well. The plate was spun at1000 rpm to settle all solution down to the wells, and then sealed at250 rpm and 25° C. for 2 minutes. Emission of the solution at each wellwas measured by a Victor™3 micro-plate reader at Excitation 400nm/Emission 445 nm and 520 nm. The emission ratio and phosphorylation(“Phos.”) percentage were calculated by the following equations:

$\mspace{20mu} {{{Emission}\mspace{14mu} {Ratio}} = \frac{{Coumarin}\mspace{14mu} {Emission}\mspace{14mu} \left( {445\mspace{14mu} {nm}} \right)}{{Fluorescein}\mspace{14mu} {Emission}\mspace{14mu} \left( {520\mspace{14mu} {nm}} \right)}}$${\% \mspace{14mu} {Phosphorylation}} = {1 - \frac{\left( {{Emission}\mspace{14mu} {Ratio} \times F_{100\%}} \right) - C_{100\%}}{\left( {C_{0\%} - C_{100\%}} \right) + \left\lbrack {{Emission}\mspace{14mu} {Ratio} \times \left( {{F\; 100\%} - {F\; 0\%}} \right)} \right\rbrack}}$

-   -   where:    -   C_(100%)=Average Coumarin emission signal of the 100% Phos.        Control    -   C_(0%)=Average Coumarin emission signal of the 0% Phos. Control    -   F_(100%)=Average Fluorescein emission signal of the 100% Phos.        Control    -   F_(0%)=Average Fluorescein emission signal of the 0% Phos.        Control        The inhibition ratio was calculated as follows:

Inhibition %=(Phos. in C2 well−Phos. in test well)/(Phos. in C2well)×100%

The result showed that all of the tested compounds inhibited theactivity of KDR.

The IC₅₀ values ranged from 0.001 to 10 μM.

Other Embodiments

All of the features disclosed in this specification may be combined inany combination. Each feature disclosed in this specification may bereplaced by an alternative feature serving the same, equivalent, orsimilar purpose. Thus, unless expressly stated otherwise, each featuredisclosed is only an example of a generic series of equivalent orsimilar features.

From the above description, one skilled in the art can easily ascertainthe essential characteristics of the present invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. For example, compounds structurally analogous to thecompounds of this invention can be made and used to practice thisinvention. Thus, other embodiments are also within the claims.

1.-25. (canceled)
 26. A method of treating an angiogenesis-relateddisorder comprising administration to a subject in need thereof aneffective amount of a compound of the following formula:

and/or a pharmaceutically acceptable salt thereof, in which each of Xand Y, independently, is O, S, or NR, wherein R is H, alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkylcarbonyl,alkoxycarbonyl, aminocarbonyl, or aminosulfonyl; Z is CR′, wherein R′ isH, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkyl, alkenyl,alkynyl, aryl, cycloalkyl, or heterocycloalkyl; V, U, and T togetherrepresent

each of R₁, R₂, R₃, R₄, and R₆, independently, is H, halo, nitro, amino,cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy,alkoxycarbonyl, carbonylamino, sulfonylamino, aminocarbonyl, oraminosulfonyl; R₅ is alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl; and R₇ is alkyl.
 27. The method of claim 26, wherein X is O.28. The method of claim 27, wherein Y is NH.
 29. The method of claim 28,wherein R′ is H, halo, or alkyl.
 30. The method of claim 29, wherein R₆is H and R₇ is methyl.
 31. The method of claim 30, wherein R₅ is aryl orheteroaryl, optionally substituted with halo, nitro, amino, cyano,hydroxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, alkoxy, alkylthio, alkylcarbonyl, carboxy, alkoxycarbonyl,sulfonyl, carbonylamino, sulfonylamino, aminocarbonyl, or aminosulfonyl.32. The method of claim 26, wherein R′ is H, halo, or alkyl.
 33. Themethod of claim 32, wherein R₆ is H and R₇ is methyl.
 33. The method ofclaim 26, wherein R₅ is aryl or heteroaryl, optionally substituted withhalo, nitro, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, alkylthio,alkylcarbonyl, carboxy, alkoxycarbonyl, sulfonyl, carbonylamino,sulfonylamino, aminocarbonyl, or aminosulfonyl.
 34. The method of claim26, wherein Y is NH.
 35. The method of claim 26, wherein the compound isselected from

and/or a pharmaceutically acceptable salt thereof.
 36. The method ofclaim 26, wherein the angiogenesis-related disorder is cancer orage-related macular degeneration.